The results of a seismo-stratigraphic study performed to study the Holocene sedimentary infilling at the mouth of the Seine River are presented. Combined data comprise very high resolution seismic reflection profiles, vibrocores, up to 4.5 m long, radiocarbon dating and old bathymetric charts. The infill is divided into two main stages: the transgressive systems tract, relative to the early Holocene high rate of sea-level rise, from 9000 to 7000 cal B.P., made of fine-grained, organic-rich, tidal flat to swamp deposits; the highstand systems tract, relative to the middle to late Holocene low rate of sea-level rise, from 7000 to 3000 cal B.P., characterized by the development of the high energy estuarine body above the main axis of the incised valley. Simultaneously, on the southern edge of the valley, a coastal barrier constructed above a bedrock plateau under the dominant action of waves. At 3000 cal B.P., probably in relation to a major climatic deterioration, the destruction of the barrier occurred and the tidal estuarine body expanded finally over the whole incised valley area. The rate of sea-level rise and the bedrock morphology appear to be the two main key-factors that control the sedimentary infilling architecture of this macrotidal, tide-dominated estuarine setting at the pluri-millenium Holocene time scale. Also, rapid climate changes determine part of the infill pattern, especially during the late Holocene sea-level highstand context.