Built as an enlarged and pressurised DC-4 in order to compete with the Lockheed Constellation, the DC-6 (as the XC-112A) first flew on 15 February 1946. It had a 2.06m longer fuselage than the DC-4, accommodation for 48-52 passengers and was powered by four 1,565kW Pratt & Whitney Double Wasp CA15 engines. American Airlines and United Air Lines introduced the DC-6 on 27 April 1946. A total of 175 DC-6 were built. The windowless DC-6A freighter followed in 1949, powered by 1,788.5kW Double Wasps, with reinforced floor and double cargo doors - 74 were built.

The DC-6A was 1.52m longer than the DC-6 (101 going to the USAF as C-118A transports). The DC-6B, with accommodation for 54-102 passengers, first flew on 2 February 1951 and also had the longer fuselage. American Airlines introduced DC-6B on its US transcontinental services on 29 April 1951. It was one of the finest and most economical piston-engined transports. It remained in production until 1958 and 288 were built. Many of the DC-6 series were later converted to freighters.