Human hepatocyte growth factor (hHGF) is a powerful inducer of angiogenesis. We investigated the relationship between serum hHGF concentrations and proliferative diabetic retinopathy, the major characteristic of which is retinal neovascularization. Serum hHGF concentrations were measured in diabetic (n = 135) and nondiabetic subjects (n = 80). The mean serum hHGF concentration in diabetic subjects without retinopathy was lower than that in nondiabetic subjects [0.041 +/- 0.003 ng/mL (n = 62) vs. 0.080 +/- 0.010 ng/mL (n = 80); P < 0.05], but was not different from that in diabetic subjects with background retinopathy (0.058 +/- 0.007 ng/mL; n = 26) or preproliferative retinopathy (0.048 +/- 0.010 ng/mL; n = 10). The mean serum hHGF concentration was increased in subjects with proliferative retinopathy who had not undergone photocoagulation (0.213 +/- 0.025 ng/mL; n = 24), but not in those who had undergone photocoagulation (0.040 +/- 0.008 ng/mL; n = 13). Circulating hHGF may be involved in the mechanism of neovascularization in the proliferative diabetic retinopathy, and measurement of serum hHGF may be helpful in predicting the presence of proliferative retinopathy in diabetic subjects.