Sedimentologic, biostratigraphic, and isotopic geochemical data from a nearly continuous 91.4 m core and high-resolution seismic-reflection data from the middle to outer shelf east of the Mississippi River delta document deposition during changes in latest Quaternary sea levels. The data suggest that the shelf edge of the northern Gulf of Mexico is constructed from deltas deposited during falling sea level and lowstands, from sediment deposited in valleys during rising sea level, and from highstand clay. The Main Pass Block 303 core records sedimentation from the late middle Pleistocene (before ca. 135 ka) to the present. A lower delta-front interval was sampled at the core base (78.5–91.4 m). Delta sediment is truncated by a sequence boundary probably eroded during maximum glaciation corresponding to oxygen isotope stage 6 (late Illinoian?) and then modified during the following transgression. Above the sequence boundary is a transgressive shelf sand (77.2–78.5 m), overlain by burrowed, hemipelagic clay (∼63.4–77.2 m). The sand and clay were deposited during postglacial sea-level rise and a highstand. The rise and highstand correspond to oxygen isotope stage 5 and Ericson zone X and part of Ericson zone Y Sangamonian-“Eowisconsinan”). The clay interval from ∼51.8 to 63.4 m depth, in turn, was likely deposited during oxygen isotope stages 3 and 4 during the early and middle Wisconsinan. Overlying, with a transitional contact, is a relatively thick mud and sand (16 to ∼51.8 m) deposited during the subsequent sea-level fall to the maximum late Wisconsinan lowstand (oxygen isotope stage 2). The mud and sand interval correspond to steeply dipping clinoforms on seismic-reflection records. An interpreted sequence boundary, formed during fluvial incision of the shelf during the maximum late Wisconsinan lowstand, separates deltaic sediment from overlying fluvial, bay, and marsh deposits, which fill an incised valley. Thin, regressive delta and shelf facies overlie the valley fill. Sediment above the sequence boundary (above 16 m) was deposited during the rise in sea level from the maximum late Wisconsinan lowstand to the present. Late Wisconsinan deltaic and overlying incised-valley-fill sediment was derived from an ancestral river system that drained the southeastern United States.