The large number of participants (5,485 patients) in the Hypertension Detection and Follow-Up Program, Stepped Care, form the largest group to date on which detailed surveillance of long-term antihypertensive therapy and drug side effects has been reported. Over a five-year period, among all hypertensive persons (mild, moderate, and severe combined) who were not taking antihypertensive medications at the beginning of the study and who attended the clinic at least once during the five-year trial, a total of 9.3% had definite or probable side effects severe enough to cause discontinuation of the drug treatment in question. An additional 23.4% had drug treatment discontinued due to possible side effects. Within the mild, moderate, and severe hypertension categories, 8.6%, 11%, and 12%, respectively, had definite or probable side effects. The incidence of side effects declined over the five years in all race-sex groups. Five-year incidence of total side effects was 29.8% in those aged 60 to 69 years at entry and 38.0%, 36.8%, and 34.1%, respectively, in those aged 50 to 59, 40 to 49, and 30 to 39 years. Sexually related side effects required discontinuation of treatment in 8.3% of male participants. However, less than 1% of active participants required hospitalization for side effects. No death that could be attributed to side effects was detected. Thus, the Hypertension Detection and Follow-up Program data, which have previously demonstrated the beneficial effects of antihypertensive therapy, confirm the relative safety of such therapy.