The long-term efficacy and safety of once-daily treatment with doxazosin or atenolol were compared in a 5-year study in patients with mild-to-moderate hypertension. The study consisted of a 1-year, multicenter, double-blind, parallel-group phase, followed by a 4-year, open-label extension phase. Of the 228 patients enrolled, 100 patients (54/111 doxazosin and 46/117 atenolol) completed the 5-year study. Both treatments were similarly efficacious in controlling blood pressure. As assessed by the Framingham risk equation, which incorporates lipid parameter values, patients receiving doxazosin had significantly less chance of developing coronary heart disease (CHD) within 10 years compared with those patients receiving atenolol (p < 0.05). Doxazosin significantly (p=0.0005) reduced the mean CHD risk from baseline to final visit by 12.3%; whereas, atenolol produced essentially no change in mean risk (0.2% increase). In patients receiving doxazosin, statistically significant (p < 0.05) increases from baseline were observed in serum concentrations of high-density lipoprotein (HDL) cholesterol and the HDL/total cholesterol ratio during the first 2 and 3 years of treatment, respectively. In contrast, significant (p < 0.05) percent reductions from baseline in both these lipid parameters were seen in atenolol-treated patients during most of the 5-year trial. Between-group differences were statistically significant (p < 0.01) at all time points. Decreases in total cholesterol were similar between the two treatment groups. Triglycerides, however, significantly increased with atenolol treatment (p < 0.0001 vs baseline) while remaining essentially unchanged with doxazosin treatment. The safety profiles of doxazosin and atenolol were comparable. Thus, while demonstrating similar antihypertensive efficacy and safety during this 5-year study, once-daily treatment with doxazosin produced a significantly greater beneficial effect on both 10-year CHD risk and serum lipid parameters compared with atenolol.