To determine whether sex-linked factors are important in the susceptibility and resistance of cynomolgus monkeys to type II collagen-induced arthritis, we immunized 5 males and 10 females with chick type II collagen (CII) and studied their clinical and immune responses. All 10 females developed overt arthritis and produced antibodies to CII and cross-reactive antibodies to monkey type II collagen (MkII). In contrast, only 1 male monkey developed arthritis, which was transient and mild in severity. Examination of antisera obtained from the male monkeys disclosed high titers of antibody to CII, but little antibody to MkII. The cyanogen bromide peptide recognition patterns varied markedly from animal to animal, implying that monkeys are capable of recognizing multiple arthritogenic determinants on CII.