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In season 4 Sam Seaborn contests the election for the California 47th congressional district as the Democratic nominee. He is replaced as Deputy Director of Communications by Will Bailey, with Toby Ziegler suggesting that Sam be given a promotion to Senior Advisor to the President if he loses the election. Sam does lose the election, however he never returns to the Bartlet administration afterwards.

Is an in-universe justification ever given for why he doesn't return to the White House afterwards? I don't remember one being given in the show itself, but is one given in interviews, directors' commentaries, etc.

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His fate is addressed towards the end of the final season of the show. From Wikipedia:

Although Sam is mentioned occasionally following his departure — most notably calling Josh to tell him to "roll with the punches" after the latter unwittingly caused the defection of a Democratic Senator — he is not seen in the series until the last episodes of the seventh and final season, following the election of Congressman Matt Santos as President. Resolving the debate over the result of the California 47th's special election, it is implied that Sam was defeated by Congressman Webb and declined the promotion to Senior Counselor to the President that had been suggested by Toby. After summarily quitting politics, Sam remained in his home state of California and joined an unnamed law firm in Los Angeles which pays him a salary that would "make [Josh] puke".

The "real world reason" for Rob Lowe's exit from the show was apparently money:

Lowe's salary is at the heart of the dispute. He has reportedly been earning the same $75,000-an-episode paycheck since the series began in 1999 and he's upset the show's producer, Warner Brothers, wouldn't even consider giving him a raise, even though other cast members have received salary increases.

Sheen's salary recently tripled, reaching $300,000 an episode. Cast members Bradley Whitford, Richard Schiff, John Spencer and Allison Janney joined forces to successfully pressure producers for pay hikes, although they reportedly still make less than Lowe.

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    Hmmm, apparently Lowe is also the actor that isn't named in this clip, but who is said to have contributed to Sorkin leaving the show: youtube.com/watch?v=vh5AmwhuPLc – BCdotWEB Jul 23 '17 at 18:50

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