The effect of extreme salinities on survival, body water percentage, condition index, leucine aminopeptidase-I (LAP) enzyme activity and allelic frequencies at the LAP-2* and LAP-3* loci of C. rhizhophorae, were studied. Sudden exposure caused 46.5% mortality at 5 PSU and 45.25% at 60 PSU after 96 hours. The highest values of body water were 82.18±0.16% at 5 PSU followed by 77.28±0.03% at 38 PSU and 74.25±0.10% at 60 PSU. The highest average value of enzymatic activity (U/mL of extract) was recorded at 60 PSU (576.160±33.135), the intermediate value at 5 PSU (432.178±26.705) and the lowest value at 38 PSU (364.146±16.115). Comparison of allelic frequencies among the surviving oysters at the three salinities tested revealed a significant dependence on salinity (p <0.05) for both LAP-2* and LAP-3*. For LAP-2*, the frequency of allele 102 was significantly represented in extreme salinities, contributing 82.36% of the difference to the total value of χ2, while for LAP-3* a proportional increase in the frequency of allele 104 and the decrease in the frequency of allele 100 was evidenced at 60 PSU and the contributions to the total value of χ2 were 35.24% and 55.65%, respectively. The results provide important support for the hypothesis that LAP variability would be the result of the selective effect of environmental salinity in this mollusk and expand the evidence on the role of this enzyme to face salinity stress in marine bivalves.