The effect of sex on longitudinal changes in serum C-peptide immunoreactivity (CPR) response to the oral glucose tolerance test (OGTT) was examined up to 48 mo in 30 islet cell antibody-positive (ICA+), non-insulindependent diabetes mellitus (NIDDM) subjects (15 men, 15 women) who were matched for age, duration of diabetes, and mode of treatment. The subjects were recruited from 2858 NIDDM patients screened for ICA between 1980 and 1984. In male NIDDM subjects, CPR levels to OGTT decreased insidiously, and 8 of 15 men developed the insulin-dependent state with abolished CPR. Only 2 female NIDDM subjects progressed to the insulin-dependent state (P < .05, women vs. men). Thus, CPR in female subjects tended to decrease less than in male subjects. There were no significant differences between the two groups in human leukocyte antigens (HLA) or titer of ICA during the follow-up period. These results suggest that maleness is a major risk factor for slowly progressive β-cell dysfunction in adult-onset insulin-dependent diabetes mellitus (IDDM).