Several epidemiologic studies reported that persons with renal insufficiency might have increased cardiovascular disease-related mortality rates in select populations. The association between renal insufficiency and increased cardiovascular disease-related and all-cause mortality rates during 16 yr of follow-up monitoring was examined among participants who were 30 to 74 yr of age at the baseline examinations in 1976 to 1980, with urinary protein dipstick measurements (n = 8786) or serum creatinine levels of <or=3.0 mg/dl (n = 6354), from the Second National Health and Nutrition Examination Survey Mortality Study. GFR were estimated by adjusting serum creatinine levels for age, race, and gender, using the Modification of Diet in Renal Disease formula. Cardiovascular disease-related mortality rates were 6.2, 17.9, and 37.2 deaths/1000 person-yr among subjects with urinary protein levels of <30, 30 to 299, and >or=300 mg/dl and were 4.1, 8.6, and 20.5 deaths/1000 person-yr among participants with estimated GFR of >or=90, 70 to 89, and <70 ml/min, respectively. After adjustment for potential confounders, the relative hazards (and 95% confidence intervals) for cardiovascular disease-related death were 1.57 (0.99 to 2.48) and 1.77 (0.97 to 3.21) among subjects with urinary protein levels of 30 to 299 and >or=300 mg/dl, respectively, compared with <30 mg/dl (P trend = 0.02). The corresponding relative hazards for all-cause-related death were 1.64 (1.23 to 2.18) and 2.00 (1.13 to 3.55; P trend < 0.001). Compared with subjects with estimated GFR of >or=90 ml/min, those with estimated GFR of <70 ml/min exhibited higher relative risks of death from cardiovascular disease and all causes [1.68 (1.33 to 2.13) and 1.51 (1.19 to 1.91), respectively]. This study indicates that, in a representative sample of the United States general population, renal insufficiency is independently associated with increased cardiovascular disease-related and all-cause mortality rates.