The purpose of this study was to investigate the concentrations of interferon (INF)-γ and tumor necrosis factor (TNF)-α in sera and tissues of patients with uterine leiomyoma and to compare the levels with those in age-matched, normally cycling women with normal sized uteri, and to evaluate their relationship, if any, to uterine weight and volume. Levels of INF-γ and TNF-α were measured by the enzyme-linked immunosorbent assay (ELISA). Comparisons were made using a nonparametric Mann-Whitney test. Linear regression analysis was performed by condition. A p value < 0.05 was considered statistically significant. Although INF-γ concentrations were higher in patients with uterine leiomyoma than in normal women, the differences were statistically nonsignificant (p > 0.05). TNF-α concentrations were significantly (p < 0.0001) higher in sera of patients with uterine leiomyoma than in sera of normal women. Circulating levels of INF-γ but not of TNF-α correlated significantly (p < 0.0001) with leiomyomatous uterine weight and volume. INF-γ and TNF-α were also detected in myomatous tissues in concentrations substantially higher than in the serum. These results indicate that TNF-α may have either a direct or an indirect role in the pathogenesis of uterine leiomyoma and possibly in its subsequent neoplastic transformation to leiosarcoma by modulating the signal transduction mechanism(s) or the hormonal action on uterine myometrial cells.