Drug interactions have become an increasingly complex challenge for treating patients with HIV infection. The present study was to evaluate the effect of efavirenz and ritonavir have any influence on the pharmacokinetics of losartan. Oral treatments of rat with efavirenz [100mg/kg] from days 1 to 13 days. On 14th day administration of efavirenz followed by Losartan [10mg/Kg] after 30 minutes. In addition ritonavir [100mg/Kg] followed similarly as efavirenz on 14th day administration of ritonavir + losartan followed after 30 minutes. Samples were estimated by reverse phase HPLC- UV method. Our study results shows that single dose of studies of efavirenz with losartan increase the bioavailability of Losartan in smaller amounts. In multiple dose studies efavirenz decrease the bioavailability of Losartan there by decrease the antihypertensive effect. Whereas, ritonavir produces antagonist effect. Hence, we conclude that drug interaction takes place with antiretroviral drug Incombination with antihypertensive therapy. In future, our clinical research with HIV patients to confirm the possibility of drug-drug interactions.