Microalbuminuria is a marker of increased risk of cardiovascular mortality in type 1 and type 2 diabetes, and in non-diabetic subjects. Little is known about the association between prospective changes of microalbuminuria and the risk factors of atherosclerosis, or gene polymorphism in non-diabetic subjects. We conducted a 6-year prospective study of risk factors for progression of albuminuria in non-diabetic subjects. The participants were 116 non-diabetic subjects who consecutively underwent medical examinations for Japanese-Americans living in Hawaii. In the baseline examination in 1992, normoalbuminuria was found in all subjects. After 6 years, 101 subjects remained normoalbuminuria (non-progressors), 15 subjects changing from normoalbuminuria to microalbuminuria or proteinuria and were defined as progressors. In progressors, compared with non-progressors, the fasting insulin level and HOMA-R were significantly higher at 3 years follow-up, and the systolic and diastolic pressure and Sigma insulin level were significantly higher at 6 years follow-up. Insulin resistance appeared earlier than the appearance of hypertension and albuminuria. In progressors, there was no significant correlation with angiotensin-converting enzyme (ACE) genotype or angiotensinogen (AGT) genotype compared with non-progressors. Therefore, the appearance of insulin resistance should be regarded as a remarkable mediator of albuminuria.