Two novel analytic methods to evaluate the roles of the HLA alleles of the human major histocompatibility complex in disease predisposition have been formulated and applied to insulin-dependent diabetes mellitus (IDDM). The HLA-DR antigens, as they are presently defined, are shown not to directly predispose individuals to IDDM. This result does not discount the possibility that subdivision of the DR antigens will yield the predisposing agents. In Caucasian populations, after consideration of the predisposing effect of the antigens DR3 and DR4, the protective effect of DR2 in predisposition is demonstrated. Additionally, DR1 and possibly DRw8 exhibit a higher than expected frequency in patients.