First flown on 29 March 1934, the S-42 was a large 36-passenger commercial flying-boat powered by four 559kW Pratt & Whitney Hornet engines. It differed from earlier Sikorsky flying-boats in having a two-step hull with a long stern which supported the tail unit directly. Full use was made of a hydraulically controlled wing flap which extended across the straight portion of the wing. Within a brief period of time the S-42 had established ten altitude-with-load world records.

Ten S-42s were delivered to Pan American Airways, the last three as S-42Bs with increased wing span (from 34.8m) and loaded weight and incorporating refinements in fairing and hull design. The original S-42 was used in survey flights across the Pacific in 1935 by Pan American Airways. In 1937 an S-42B surveyed the route from San Francisco to New Zealand, via Honolulu; a similar aircraft was used on the inaugural and scheduled mail and passenger service between New York and Bermuda, the latter shared with Imperial Airways and begun on 16 June 1937. At about the same time the final S-42B delivered to PAA (named Clipper III) made three survey flights across the Atlantic by way of Newfoundland and Foynes.