A realistic modeling approach is designed to address the role of winter mixing on the interannual variability of plankton dynamics in the north-western (NW) Mediterranean basin. For the first time, a high-resolution coupled hydrodynamic-biogeochemical model (Eco3m-S) covering a 30-year period (1976-2005) is validated on available in situ and satellite data for the NW Mediterranean. In this region, cold, dry winds in winter often lead to deep convection and strong upwelling of nutrients into the euphotic layer. High nutrient contents at the end of winter then support the development of a strong spring bloom of phytoplankton. Model results indicate that annual primary production is not affected by winter mixing due to seasonal balance (minimum in winter and maximum in spring). However, the total annual water column-integrated phytoplankton biomass appears to be favored by winter mixing because zooplankton grazing activity is low in winter and early spring. This reduced grazing is explained here by the rarefaction of prey due to both light limitation and the effect of mixing-induced dilution on prey/predator interactions. A negative impact of winter mixing on winter zooplankton biomass is generally simulated except for mesozooplankton. This difference is assumed to stem from the lower parameterized mortality, top trophic position and detritivorous diet of mesozooplankton in the model. Moreover, model suggests that the variability of annual mesozooplankton biomass is principally modulated by the effects of winter mixing on winter biomass. Thus, interannual variability of winter nutrient contents in the euphotic layer, resulting from winter mixing, would control spring primary production and thus annual mesozooplankton biomass. Our results show a bottom-up control of mesozooplankton communities, as observed at a coastal location of the Ligurian Sea.