Dopamine receptors are important in systemic blood pressure regulation. D ₄ receptors are expressed in the kidney and brain, but their role in cardiovascular regulation is unknown. In pentobarbital-anesthetized mice, systolic and diastolic blood pressures were elevated in sixth-generation D ₄ receptor–deficient (D ₄ ^−/− ) mice and in tenth-generation D ₄ ^−/− mice compared with D ₄ wild-type (D ₄ ^+/+ ) littermates. The conscious blood pressures measured via a chronic arterial (femoral) catheter or telemetry (carotid) were also higher in D ₄ ^−/− mice than in D ₄ littermates. Basal renal and plasma renin concentrations were similar in the 2 mouse strains. The protein expression of angiotensin II type 1 receptor was increased in homogenates of kidney (330±53%, n=5) and brain (272±69%, n=5) of D ₄ ^−/− mice relative to D ₄ ^+/+ mice (kidney: 100±12%, n=5; brain: 100±32%, n=5). The expression of the receptor in renal membrane was also increased in D ₄ ^−/− mice (289±28%, n=8) relative to D ₄ ^+/+ mice (100±14%, n=10). In contrast, the expression in the heart was similar in the 2 strains. Bolus intravenous injection of angiotensin II type 1 receptor antagonist losartan initially decreased mean arterial pressures to a similar degree in D ₄ ^−/− and D ₄ ^+/+ littermates. However, the hypotensive effect of losartan dissipated after 10 minutes in D ₄ ^+/+ mice, whereas the effect persisted for >45 minutes in D ₄ ^−/− mice. We conclude that the absence of the D ₄ receptor increases blood pressure, possibly via increased angiotensin II type 1 receptor expression.