The diagnosis of drowning is considered one of the most difficult in forensic medicine. Due to the paucity of signs, it is a classical diagnosis by exclusion. For this reason, specific immunohistochemical markers would be useful. Far too little has been done to analyze in-depth the differences between SWD and FWD. We focused on the renal immunohistochemical expression of aquaporin 2, AVP, V2R, and renin in cases of drowning. This study has two purposes: (1) to better understand the differences between saltwater drowning (SWD) and freshwater drowning (FWD), which may indicate different pathophysiology and (2) to eventually identify markers useful for the diagnosis of drowning. We retrospectively investigated 10 cases of SWD gathered from the Institute of Legal Medicine in Genoa (Italy), and 10 cases of FWD from the University Center of Legal Medicine in Geneva (Switzerland). As a control group, we investigated 10 cases of death by gunshot to the head. A strong expression of AQP2 and AVP was significantly (p < 0.05) more evident in cases of SWD than in FWD and control cases. Regarding the V2R, no statistically significant differences were found between the studied groups. The renin tubular expression was particularly intense (p < 0.05) both in SWD and in FWD compared controls. According to our results, AQP2 and AVP represent potential useful markers for the differential diagnosis between SWD and other causes of death, including FWD. Renin may be a useful marker in the diagnosis of drowning but it does not allow for differentiation between FWD and SWD.