Background: In autosomal dominant polycystic kidney disease, renoprotective treatment with a vasopressin V2 receptor antagonist (V2RA) is given in a fixed dose (FD). Disease progression and drug habituation could diminish treatment efficacy. We investigated whether the renoprotective effect of the V2RA can be improved by dose titration of the V2RA aiming to maintain aquaresis at a high level. Methods: The V2RA OPC-31260 was administered to Pkd1-deletion mice in an FD (0.1%) or in a titrated dose (TD, up to 0.8% when drinking volume dropped). Total kidney weight (TKW) and cyst ratio were investigated and compared to non-treated Pkd1-deletion mice. Treatment was started early or late (21 or 42 days postnatal). Results: Water intake was significantly higher throughout the experiment in the TD compared to the FD group. FD treatment that was initiated early reduced TKW and cyst ratio but lost its renoprotective effect later during the experiment. In contrast, TD treatment was able to maintain the renoprotective effect. TD treatment, however, was also associated with a higher early termination rate in comparison with FD treatment. Late start of treatment (FD or TD) did not show a renoprotective effect. Conclusions: Titration of a V2RA aimed to maintain aquaresis at a high level showed a better renoprotective effect compared to FD administration. However, this treatment regimen was poorly tolerated and did not overcome treatment unresponsiveness when started later in the disease.