Background: Inactivating mutations of the V2 receptor (V2R) cause nephrogenic diabetes insipidus (NDI). Results: Two V2R mutants discovered in partial NDI show partial defects, and V2R antagonists rescued them. Conclusion: V2R antagonists operate as pharmacochaperones for defective mutants, whereas they operate as inverse agonists for normal receptors. Significance: V2R antagonists can act as protean agonists, potentially underlying their dual effects.