The purpose of this study was to evaluate the Safety and efficacy of the orally administered protein kinase C (PKC) beta isoform-selective inhibitor ruboxistaurin (RBX) in subjects with moderately severe to very severe nonproliferative diabetic retinopathy (NPDR). In this multicenter, double-masked, randomized, placebo-controlled study, 252 subjects received placebo or RBX (8, 16, or 32 mg/day) for 36-46 months. Patients had an Early Treatment Diabetic Retinopathy Study (ETDRS) retinopathy severity level between 47B and 53E inclusive, an ETDRS visual acuity of 20/125 or better, and no history of scatter (panretinal) photocoagulation. Efficacy measures included progression of DR, moderate visual loss (MVL) (doubling of the visual angle), and sustained MVL (SMVL). RBX was well tolerated without significant adverse effects but had no significant effect on the progression of DR. Compared with placebo, 32 mg/day RBX was associated with a delayed occurrence of MVL (log rank, P = 0.038) and of SMVL (P = 0.226). RBX reduction of SMVL was evident only in eyes with definite diabetic macular edema at baseline (10% 32 mg/day RBX vs. 25% placebo, P = 0.017). In multivariable Cox proportional hazard analysis, 32 mg/day RBX significantly reduced the risk of MVL compared with placebo (hazard ratio 0.37 [95% CI 0.17-0.80], P = 0.012). In this clinical trial, RBX was well tolerated and reduced the risk of visual loss but did not prevent DR progression.