A 7.38 m-long sediment core was collected from the eastern part of the Rhone prodelta (NW Mediterranean) at 67 m water depth. A multi-proxy study (sedimentary facies, benthic foraminifera and ostracods, clay mineralogy, and major elements from XRF) provides a multi-decadal to century-scale record of climate and sea-level changes during the Holocene. The early Holocene is marked by alternative silt and clay layers interpreted as distal tempestites deposited in a context of rising sea level. This interval contains shallow infra-littoral benthic meiofauna (e.g. Pontocythere elongata, Elphidium spp., Quinqueloculina lata) and formed between ca. 20 and 50 m water depth. The middle Holocene (ca. 8.3 to 4.5 ka cal. BP), is characterized, at the core site, by a period of sediment starvation (accumulation rate of ca. 0.01 cm yr−1) resulting from the maximum landward shift of the shoreline and the Rhone outlet(s). From a sequence stratigraphic point of view, this condensed interval, about 35 cm-thick, is a Maximum Flooding Surface that can be identified on seismic profiles as the transition between delta retrogradation and delta progradation. It is marked by very distinct changes in all proxy records. Following the stabilization of the global sea level, the late Holocene is marked by the establishment of prodeltaic conditions at the core site, as shown by the lithofacies and by the presence of benthic meiofauna typical of the modern Rhone prodelta (e.g. Valvulineria bradyana, Cassidulina carinata, Bulimina marginata). Several periods of increased fluvial discharge are also emphasized by the presence of species commonly found in brackish and shallow water environments (e.g. Leptocythere). Some of these periods correspond to the multi-decadal to centennial late Holocene humid periods recognized in Europe (i.e. the 2.8 ka event and the Little Ice Age). Two other periods of increased runoffs at ca. 1.3 and 1.1 ka cal. BP are recognized, and are likely to reflect periods of regional climate deterioration that are observed in the Rhone watershed.