Mortality in insulin-dependent diabetes is markedly increased compared to the general population. Although strong associations have been found between renal disease and the risk of cardiovascular disease (CVD) the interaction between these two factors is not well understood. This study, which addresses risk factors for mortality in IDDM with a particular focus on the renal-CVD link, is based on the prospective Epidemiology of Diabetes Complications study. Thirty-seven (mean age 36 years, mean duration of IDDM 28 years at baseline) of the 658 IDDM individuals (mean age 28 years, mean duration of IDDM 20 years at baseline) have died in the first 4 years of follow up. A nested case-control study was performed, matching on sex and duration of diabetes. Twenty-two (59%) of the deaths were attributed to coronary heart disease, with an additional 16% attributed to diabetic coma. Only nine (41%) of the 22 individuals who died from cardiovascular disease had clinical evidence of coronary heart disease when seen for their last biennial exam. However, 54% of those who died of CVD without prior evidence did have evidence of lower extremity arterial disease. A strong link with renal disease was confirmed, with 81% of those with a coronary artery disease death having renal disease. Multivariate analyses suggest that smoking history, triglycerides and total platelet count are independent predictors of mortality, while LDL cholesterol best predicted CVD mortality. These results suggest a need for more intensive screening for cardiovascular disease, and correction of cardiovascular risk factors, in order to reduce the increased rate of mortality in this population. Efforts to prevent or delay the onset of renal disease may also be of benefit.