In IDDM an association between diabetic retinopathy and polymorphic markers of MHC has been described. However, these associations are complicated by a primary association between the MHC and IDDM. Because the pathogenesis of retinopathy is likely to be the same in IDDM and NIDDM, NIDDM subjects with retinopathy would be the ideal population to study for an association with MHC markers. The following South Indian subjects were therefore studied: unselected NIDDM (n = 76), unselected IDDM (n = 99), non-diabetic controls (n = 96), NIDDM subjects with maculopathy (MAC), n = 55, NIDDM subjects with proliferative retinopathy (PR), n = 53, and without retinopathy (LTD), n = 46. DNA was amplified and studied using a microsatellite polymorphism located 3.5 kb upstream of TNF-beta within the MHC class III region on the short arm of chromosome 6. No differences in allelic distribution were observed between the random NIDDM subjects and controls (p = 0.17). Differences in allelic distribution were found between unselected IDDM and controls (P = 0.016) and between the NIDDM subjects with maculopathy and/or proliferative retinopathy and no retinopathy (P = 0.006). This association could be accounted for by those patients with proliferative retinopathy (MAC vs LTD, p = 0.23; MAC vs PR, p = 0.07; and PR vs LTD, p = 0.002).