KTUU is one of the first two TV stations to sign on in Alaska (the other being CBS affiliate KTVA, channel 11), signing on October 16, 1953, as KFIA. It became KENI-TV in 1955, and then KTUU on June 10, 1981.

On September 19, 1966, channel 2 became the first station in Alaska to transmit in color when it aired the premiere episode of the ABC sitcom That Girl (entitled "Don't Just Do Something, Stand There!"). The station had joint primary affiliation with NBC and ABC (with KTVA picking up some of the slack) until October 1, 1967, when it switched to ABC primary and NBC secondary, primarily because ABC had more programs on film. Channel 2 became a full-time ABC affiliate in 1970 when KHAR (channel 13, now KYUR) took the NBC affiliation. The two stations switched networks in October 1971, at which time KHAR became KIMO. Channel 2 also carried a few PBS programs (particularly The Electric Company) until KAKM signed on in 1975. Until KTVF in Fairbanks switched networks from CBS to NBC in April 1996, KTUU was the only full-time NBC affiliate in Alaska, clearing every network program.

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