The objective was to evaluate the dose-related efficacy/tolerance profile of 240, 300, 360, and 420 mg diltiazem slow-release, once-daily (OD) doses, with emphasis on the 300 mg dose. The study was randomized and double-blinded with a 36-week parallel, two-branched, cross-over design after a single-blind, run-in period of 4 weeks on placebo and 6 weeks on 300 mg diltiazem OD. Each branch included six 6-week active treatment periods with 180, 240, and 300 mg tablets, one or two tablets OD. Participants were men and postmenopausal women, aged 40-70 years, with uncomplicated primary hypertension (WHO stages I and II) and a supine diastolic blood pressure of 95-115 mm Hg in the absence of antihypertensive medication. A total of 138 patients from various clinics participated in the study. All were included in the intention to treat analysis, and 117 patients were included in the per protocol analysis. Criteria for evaluation were blood pressure, heart rate, and response rate, as well as plasma diltiazem and metabolite M1 concentration before morning dose. Well-being of the patients and adverse events were recorded. Electrocardiogram and standard laboratory tests were obtained. Analysis of variance was used for statistical calculations. Supine blood pressures and response rates in the per protocol analysis were 161.2/97.0 for placebo (29.1%), 155.2/ 92.8 for 240 mg (54.7%), 153.8/91.6 for 300 mg (55.6%), 155.5/92.0 for 360 mg (59.0%), and 152.0/90.5 for 420 mg (63.2%) of diltiazem OD. The intention to treat analysis was very similar to the per protocol analysis. There was a small but statistically significant decrease in heart rate for all doses of diltiazem OD compared to placebo. A linear relationship existed between the dose and the plasma concentration of both diltiazem and metabolite M1, as well as a dose-response relationship. Diltiazem OD in the dose range 240-420 mg was generally well tolerated and not differently perceived from the placebo treatment except for ankle edema (2-6%). The study shows that OD diltiazem is significantly superior to placebo for mild to moderate hypertension and that the effect is large enough to be clinically valuable. It also shows that there is a linear dose-response relationship for diltiazem between 240 and 420 mg.