Horizontal transects of surface salinity and in-vivo fluorescence indicate the existence of three distinct spatial regimes in South San Francisco Bay. A mid-Bay region of low phytoplankton biomass with little small-scale variance is bounded to the north and south by water masses having higher in-vivo fluorescence and enhanced small-scale variability. Autocorrelation analyses demonstrate that the length scale of phytoplankton patchiness is longest in the mid-Bay region. The persistent discontinuities of in-vivo fluorescence and salinity are associated with topographic features—a large shoal to the north and a constriction to the south. The three spatial regimes are consistent with measured zooplankton distributions, existing current meter data, estimated longitudinal transports, and numerical simulations of residual circulations that show one (and perhaps two) large-scale gyre(s) bounded by the northern shoal and southern constriction. Topographic features are the most important physical factors controlling mesoscale (~ 10 km) variability of phytoplankton in South San Francisco Bay. We speculate that vertical current shear and salinity stratification (and their effects upon turbulence and diffusion) control small-scale patchiness, but quantitative estimates are needed to determine the influence of large-scale (and local) phytoplankton growth and loss processes.