A sensitive C-peptide immunoreactivity radioimmunoassay demonstrated the presence of subtle, but definite residual β-cell function in patients with IDDM of long duration. Although HLA antigens are known to influence susceptibility to IDDM, their contribution to the extent of pancreatic β-cell destruction has not yet been examined extensively. We studied the relationship between residual β-cell function and HLA class I and class II antigens in 111 unrelated Japanese IDDM patients. Using the sensitive C-peptide immunoreactivity radioimmunoassay, the presence or absence of residual β-cell function was evaluated by the C-peptide immunoreactivity response to a 100-g oral glucose load. DNA typing for HLA-DQA1 and HLA-DQB1 antigens was performed in addition to serological typing of HLA-A, HLA-B, HLA-C, and HLA-DR antigens. A C-peptide immunoreactivity response > 0.033 nM was regarded as an indication of the presence of residual β-cell function, not the assay error. Surprisingly, 35 of 37 (94.6%) patients without residual β-cell function had HLA-A24, whereas only 39 of 74 (52.7%) patients with residual β-cell function had this antigen (corrected P = 9.795 × 10(–6). Any other HLA antigens, including the DR and DQ loci, showed no difference in the frequency with regard to residual β-cell function. The duration of diabetes was similar between the groups with and without residual β-cell function. The duration of diabetes was similar between the groups with and without residual β-cell function. Even when the patients were stratified according to the duration of diabetes, HLA-A24 was more common in those with early complete loss of β-cell function (duration of diabetes <1 yr) (P = 0.035) and was less common in those with residual β-cell function despite a long duration of diabetes (>10 yr) (P = 0.001). The correlation between HLA-A24 positivity and complete β-cell loss also was confirmed in younger-onset (<30 yr old) and elder-onset (≥30 yr old) groups. The C-peptide immunoreactivity response in patients with HLA-A24 (0.09 ± 0.02 nM, mean ± SE, n = 74) was significantly lower than that in patients without HLA-A24 (0.19 ± 0.03 nM, n = 37, P < 5.0 × 10⁻⁵). Further typing of HLA-A24 by one-dimensional isoelectric focusing gel electrophoresis revealed that the isoelectric point of HLA-A24 was identical in charge in 17 of 18 patients and 7 normal control subjects (isoeletric point 6.32, HLA-A24.1). We conclude that a specific HLA class I antigen, HLA-A24, promotes pancreatic p-cell destruction in IDDM patients with other disease-susceptible HLA antigens.