This Viewpoint identifies some of the pitfalls in the bioavailability of water-soluble drugs and introduces a novel bias we term the “hypohydration bias”. We suggest that future bioavailability studies take some important neglected confounding factors into account, and we propose that, to avoid such a bias, some relevant variables such as serum and urine osmolality, dry weight adjustment, fluid balance, semi-nude body mass, saliva osmolality, saliva total protein concentration, and urine specific gravity should be controlled to increase the precision of the bioavailability measurements. We suggest that a new definition of hydration status is needed, and that systematic protocols of bioavailability studies should be revisited.