Many Tertiary species of Crassostrea appear to have inhabited shallow-marine environments where they produced extremely large and thick shells. In contrast, living Crassostrea species are restricted primarily by marine predation to brackish, hypersaline, and intertidal environments where they produce comparatively smaller and thinner shells. If Crassostrea populations have used estuarine environments as a refuge from predation since the Cretaceous, then their presence in fully marine environments after the Cretaceous is puzzling. In order to interpret differences in environment and shell size, I examined the paleoecology and sclerochronology of two marine and two estuarine populations. Results are consistent with the hypothesis that thicker shells in Tertiary Crassostrea titan deterred increased exposure to fully marine predation. Life spans and growth rates estimated from annually formed growth increments show that C. titan grew significantly faster in shell thickness, as well as lived two to three times longer, than Quaternary Crassostrea virginica. Similar or lower valve-height growth rates in C. titan, as well as thinner shell walls in the attachment area, are consistent with exposure to marine predation, but not with alternative factors, such as higher salinity or alkalinity. Thicker valves in C. titan resulted from the successive addition of chalky deposit layers, in contrast to C. virginica valves, which contain significantly less of this unusual shell structure. A high incidence of incomplete drill holes in juvenile C. titan shells demonstrates that their thick valves were successful in deterring muricid predation. The association of C. titan with other large suspension feeders (barnacles and pectenids), as well as with phosphatic-pellet sediments, suggests that elevated planktic productivity may have supported this reefal community and enabled C. titan to grow thicker shells. The occurrence of both shallow-marine and estuarine Crassostrea since the Cretaceous raises the possibility that estuaries have served as refugia from which populations have dispersed into fully marine environments multiple times through the Cenozoic.