Bardet-Biedl syndrome is a rare autosomal recessive disease characterized by dysphormic extremities, retinal dystrophy, obesity, hypogenitalism in males, and renal structural abnormalities. Because the clinical outcome of these patients is not well known, 21 families with Bardet-Biedl syndrome (BBS) were studied to determine the natural history of the disease. In a prospective cohort study, 38 patients with the syndrome and 58 unaffected siblings were identified. Patients were studied in 1987 and again in 1993. Age of onset of blindness, hypertension, diabetes, renal impairment, and death was determined. The prevalence of obesity, gonadal dysfunction, and renal structural abnormalities was assessed. All but 5 BBS patients (86%) were legally blind, 26% being blind by the age of 13 years and 50% by 18 years. Eighty-eight percent were above the 90th percentile for height and weight. Twenty-five (66%) patients had hypertension, 25% of BBS patients by age 26 years, and 50% by age 34 years, whereas in the unaffected group, 25% had hypertension by age 49 years (P < 0.0001). Twelve (32%) BBS patients developed diabetes mellitus, compared with none of the unaffected group. Only 2 patients were insulin dependent. Twenty-five percent of BBS patients had diabetes by the age of 35 years. In 12 women of reproductive age, 1 (8%) had primary gonadal failure. In 10 men, 4 had primary testicular failure. Nine (25%) patients developed renal impairment, with 25% of the BBS group affected by the age of 48 years. Imaging procedures of the kidney were performed in 25 patients with normal renal function. Whereas fetal lobulation and calyceal cysts/diverticula/clubbing were characteristic, occurring in 96% of patients, 20% (n = 5) had diffuse and 4% (n = 1) focal cortical loss. Eight patients with BBS died, 3 with end-stage renal failure and 3 with chronic renal failure. On life-table analysis, 25% of BBS patients had died by 44 years, whereas at that age 98% of unaffected siblings were still alive (P < 0.0001). Bardet-Biedl syndrome has an adverse prognosis, with early onset of blindness, obesity, hypertension, and diabetes mellitus. Renal impairment is frequent and an important cause of death. Survival is substantially reduced.