Natural variation in the physiological variables of the eastern oyster Crassostrea virginica from a tropical climate have until now been poorly documented. This study was conducted to characterize the influence of hydrological variables (salinity, temperature, nitrate, nitrite, ammonium, soluble reactive phosphorus [SRP], and soluble reactive silica [SRSi]) on oyster physiological variables (total hemocyte cells (THC), reactive oxygen intermediates (ROIs), agglutination, lysozyme, and protein concentration). Oysters were collected during 3 different months (April, August, and December) from seven sites in Terminos Lagoon SW-Mexico. The association of physiological variables with oyster condition index (CI) was also studied. The physiological variability explained by environmental variables was high (30.7%) when compared with the variability explained by the condition index (8.9%). The independent effect of salinity explained 69.7% of the total variability in the physiological variables (F-ratio = 3.4; P = 0.002, Monte Carlo test with 499 permutations). Protein concentration was significantly correlated with spatial salinity variation (r² = 0.89; H = 27.01, P < 0.0001). Site effects were salinity-protein discriminated (F-ratio = 3.406; P = 0.002). Temperature was not a significant variable in the oyster physiological variability. The oysters from marine freshwater transition zones were less affected in their CI and physiological parameters than oysters from permanent high (>28 psu) or low salinity conditions (<10 psu). This study represents the first step toward integrating specific C. virginica physiological information from tropical areas.