Basic fibroblast growth factor (bFGF) is a potent endothelial cell mitogen that does not normally circulate, but increases in microalbuminuric adult type 2 diabetes mellitus. Earlier work indicated an unexpected association between low levels of plasma bFGF immunoreactivity and the subsequent 4-year need for laser treatment in 172 patients from the Veterans Affairs Diabetes Trial (mean: age, 59 years; diabetes duration, 11 years; baseline hemoglobin A(1c), 9.5%). In the present study, we tested for an association between endothelial cell inhibitory autoantibodies in plasma and the need for laser treatment. Inhibitory activity in endothelial cells from the immunoglobulin G fractions of plasma was significantly associated (P = .002) with low plasma bFGF immunoreactivity. There was a significant association (P = .003) between endothelial cell inhibitory autoantibodies in baseline plasma and the time to occurrence of first laser treatment after 4 years of study treatment. After adjusting for other risk factors, endothelial cell inhibitory activity greater than 90% vs less than or equal to 90% (hazard ratio, 0.2; P = .003) and low-density lipoprotein cholesterol concentration (hazard ratio, 0.98; P = .02) were each significant predictors of the time to first postrandomization laser occurrence. These results suggest that circulating autoantibodies inhibitory in endothelial cells may contribute to the need for laser treatment in adult men with advanced type 2 diabetes mellitus. Among the possible risk factors evaluated, baseline insulin use was the only variable significantly inversely (P = .02) associated with the baseline occurrence of inhibitory endothelial cell autoantibodies. It could not be determined whether insulin use may decrease the occurrence of endothelial cell inhibitory autoantibodies in advancing adult type 2 diabetes mellitus.