Nine multicenter, randomized, placebo-controlled studies were conducted to evaluate the safety and tolerability of the angiotensin II subtype 1 receptor blocker (AT1 blocker) irbesartan for the treatment of mild to moderate hypertension. After a 4- to 5-week placebo lead-in phase, patients were randomized to 4 to 12 weeks of double-blind therapy with either placebo (n = 641) or irbesartan (n = 1,965) at doses of 1 to 900 mg orally. All doses of irbesartan were well tolerated with no evidence of dose-related adverse effects. Across the full recommended clinical dose range, although not statistically significantly different, irbesartan use was associated with a lower incidence of adverse events, serious adverse events, and discontinuations due to adverse events compared with placebo. No clinically significant or unexpected changes in laboratory analyses were observed. Withdrawal of irbesartan therapy did not result in rebound hypertension or clinically important adverse events. Thus, irbesartan use in hypertensive patients was associated with a placebo-like safety and tolerability profile.