Major rivers transfer high loads of continental particulate organic matter to deltaic environments, where the impact on the biogeochemistry and productivity of coastal sediments depends on the sources and lability of these inputs. Our aims are to provide new insights into the reactivity of riverine inputs in coastal environments and to delineate the parameters controlling their fate in these dynamic systems. Sediment cores were collected from a Mediterranean deltaic system (the Rhône prodelta and its adjacent shelf) during a period of moderate river discharge (Spring 2007) and analyzed for their fatty acid composition. Sediment properties were also described using biochemical bulk analyses (organic carbon and lipids), granulometry and profiles of redox potential. Based on the bulk compositional changes and hierarchical clustering of the fatty acid biomarkers, we determined the principal sources of organic matter and their spatial distribution. Fatty acids were primarily of continental origin in the prodelta, shifting to a higher contribution from marine sources in the shelf area. Fatty acids derived from both continental and marine sources were efficiently degraded in the sediments by microbial decay processes in the upper oxic layer. Degradation rate constants calculated from the down-core decreases in concentrations indicate that fatty acid degradation was enhanced in sediments influenced by the Rhône River. The most important parameters affecting fatty acid preservation were the inherent stability of individual molecular components and their physical association with mineral matrices, the source and freshness of the inputs, and the depositional environment (redox condition, accumulation rates).