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Claire met Jamie shortly after she accidentally traveled through time from 1946 to 1743. She reset his dislocated shoulder and bandaged wounds that he sustained during a skirmish with English soldiers over the course of one night, during which they rode the same horse on the way to Castle Leoch. While staying at the castle, Claire gradually learned more about Jamie's background and circumstances, namely that he had a price on his head for a crime he didn't commit and couldn't return to his family's home.

Just a few months after meeting, several weeks of which were spent on the road collecting rents with the MacKenzies, Claire was left with no better option for her survival than to marry a Scot in order to evade the grasp of Captain Randall. She married Jamie unwillingly, though over the course of their wedding night it became apparent that there was certainly more to the attraction that had been building between them than simple lust or loneliness. She took one opportunity to try to escape and return to her own time, but was foiled when she was picked up by English redcoats and brought to Captain Randall. Jamie rescued her, and they returned to Castle Leoch.

They spent several months as a married couple in the castle until Claire was imprisoned in the local village as a suspected witch. Jamie rescued her yet again, and she told him the truth about where, and when, she came from. He believed her, much to her surprise, though he admitted he didn't understand it yet. He then took her back to the stone circle at Craigh na Dun, so that she could return to her husband, Frank. Though she spent the day contemplating her decision, she ultimately chose to stay with Jamie.

They lived a few short, happy weeks at Lallybroch with Jamie's sister Jenny and her husband Ian, before Jamie was captured by redcoats in the district. Claire and Jenny, then later Claire and Murtagh tracked Jamie and made attempts to attract his attention to their location. After weeks of travel, they learned that Jamie had been captured and imprisoned at Wentworth. Claire convinced some MacKenzie men to help her rescue Jamie, and their mission was ultimately successful, though not before Jamie had suffered torture and abuse at the hands of Jack Randall. They escaped to France and stayed at the Abbey of Ste. Anne de Beaupré where Jamie's uncle was abbot. Jamie languished in despair and worsening illness until Claire employed unconventional methods to save Jamie's soul from torment, and help him begin to heal.

Learning that Claire was pregnant, and unable to return to Scotland, they decided to stay in France and try to prevent Charles Stuart from gaining traction among the Jacobites that would fund his imminent, doomed rebellion. They attended King Louis XV's court and ingratiated themselves into powerful circles, and the daily grind put a strain on their young marriage. When Captain Randall appeared in Paris, Jamie became determined to kill his abuser, but Claire begged Jamie to spare him for another year, in order to ensure her first husband, a descendant of Randall's, would still be born. He agreed at first, but after witnessing Randall in the act of molesting Jamie's young protégé, Fergus, Jamie challenged Randall to a duel with the intent to kill. Claire pursued them but arrived too late, able only to witness which of her husbands—Jamie or Frank—might die. During the fight, Claire suffered a miscarriage and later convalesced at L'Hôpital des Anges and Fontainebleau. She sought the King's favor to free Jamie from the Bastille, and upon reuniting they overcame their grief enough to reconcile and take solace in one another, and returned to Scotland with a pardon for Jamie.

They lived for a year at Lallybroch in relative peace, until Jamie was forced to join the Stuart cause and they left to join the army. Knowing the outcome—thanks to Claire's unique perspective—made witnessing the ups and downs of the campaign even more agonizing, but the strength of their bond sustained them through the war. Ultimately, however, Jamie made the anguished decision to send Claire back through the stones just before the slaughter at Culloden was due to occur, in order to save both Claire and their unborn child.

For twenty years they lived apart, neither completely their whole selves any longer, though they made significant efforts to support their families. It was not until 1968 that Claire returned to Scotland with their grown daughter, Brianna, and learned that Jamie did not die at the Battle of Culloden like he meant to. With the help of Brianna and a young historian named Roger Wakefield, they found Jamie's whereabouts in 1766, and Claire decided to go through the stones once more to find Jamie.

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