Autoimmune arthritis was induced after a single injection of the non-immunogenic adjuvant (avridine) or with autologous rat type II collagen. Females of two different rat strains, DA and LEW, were found to be more susceptible than males. To investigate further the mechanisms behind the female preponderance, we selected the avridine induced arthritis model. This is known to be a chronic joint-specific disease which is T-cell dependent and associated with MHC genes and, therefore, is an appropriate model for rheumatoid arthritis. To address the possibility of sex chromosome involvement, reciprocal F1 hybrids were produced. Female (DAxLEW)F1 rats were found to be more prone to arthritis than their male counterparts. This difference could be explained, at least partly, by the influence of sex chromosomes since reciprocal (LEWxDA)F1 rats showed no sex linkage. However, the sex linkage was more pronounced in normal rats when compared to castrated (DAxLEW)F1 rats indicating a role for sex hormones in conjunction with the sex chromosome-linked effect. Both oestrogen and testosterone had a suppressive effect on the development of arthritis. The findings presented here suggest the presence of a sex chromosome gene, which mediates its function only in the presence of sex hormones and is associated with a female preponderance for development of arthritis.