It has been hypothesized that severe psoriasis is an independent risk factor for cardiovascular disease (CVD). We prospectively studied patients with severe psoriasis treated with psoralens and ultraviolet-A therapy (PUVA) who enrolled in a cohort study in 1975-1976. From 1977 to 2005, 617 of the 1,376 patients (45%) died. Compared with the general population, cohort death rates were significantly higher than expected (standard mortality ratio (SMR) = 1.1, 95% confidence interval (CI) = 1.02-1.20). The number of deaths due to CVD (SMR = 1.02, 95% CI = 0.9-1.6) was nearly identical to the expected number. Deaths due to liver disease were significantly elevated (SMR = 4.04, 95% CI = 2.76-5.70). Patients with exceptionally severe psoriasis at entry (>42% body surface area (BSA)) had a significantly increased risk of death compared with less severely affected cohort members (all-cause hazard ratio (HR) = 1.42, 95% CI = 1.18-1.69) as well as for deaths because of causes other than cancer or CVD (multivariate HR 1.56, 95% CI = 1.14-2.13). Only patients with exceptionally severe psoriasis had an increased mortality risk compared with both the general population and other cohort members with less extensive but still severe psoriasis. These increases were not significant for CVD. Our data do not support the hypothesis that severe psoriasis is an independent risk factor for CVD. However, exceptionally severe psoriasis is associated with increased all-cause mortality.