Subsensitivity to H 1-receptor antagonists has been attributed to autoinduction of enzyme systems and increased clearance rates during chronic drug administration. We studied the changes in serum half-life values and clearance rates in dogs who were administered hydroxyzine, 0.7 mg/kg, intramuscularly, daily, for 150 days. Pharmacokinetic studies were performed on the first day of drug administration, and on days 30, 60, 90, 120, and 150. The mean serum half-life value on day 30, 60, and 120 was significantly longer ( p < 0.05) than that of 2.4 ± 0.3 hours obtained on day 1. The mean clearance values obtained on days 30, 60, 90, 120, and 150 were significantly slower ( p < 0.05) than the value of 25.12 ± 4.13 ml/min/kg obtained on day 1 but were not significantly different from each other. Mean serum hydroxyzine concentrations were often significantly higher on the later study days than on day 1. The mean apparent volume of distribution values obtained on days 30, 60, 90, 120, and 150 did not differ significantly from the value of 5.0 ± 1.5 L/kg obtained on day 1. This study adds to the mounting evidence that subsensitivity to the effects of an H 1-receptor antagonist is not due to autoinduction of enzyme systems, more rapid clearance of the drug, and lower concentrations of te drug in serum and tissue.