We investigated the relationship between changes in helplessness and depression to disease activity in rheumatoid arthritis (RA). Sixty-three men with RA were examined at baseline, 3 months, and 6 months. Joint counts, immunophenotypic analyses of peripheral blood lymphocytes, and measures of psychological status were obtained at each examination. Zero-order correlations between psychological change and disease activity change from baseline to 6 months were not significant, but hierarchical multiple regression analyses revealed that changes in affective state were significantly related to joint counts at 6 months. Additionally, changes in absolute numbers of HLA-DR+ (human leukocyte antigen DR type) cells were significantly related to joint counts at 6 months. When absolute numbers of HLA-DR+ cells were entered prior to affective state in a hierarchical multiple regression, affective state was only marginally statistically significant. The study shows that longitudinal relationships between affective changes and disease activity are moderated by intervening variables such as immunologic activation.