Thyroid hormone (TH) is important for normal reproductive function. Our previous studies indicate that FSH increases preantral follicle growth in vitro, a response markedly enhanced by triiodothyronine (T3). However, the nature of this hormonal interaction is poorly understood. The objective of this study was to determine if and how T3 modulate FSH-induced expression and actions of granulosa cell intracellular survival and death intermediates. We investigated the possible involvement of Src and PI3K/Akt pathway in the regulation of granulosa cell survival. We demonstrated that, while ineffective alone (0.1-100 nM), T3 markedly enhanced FSH (100 ng/ml)-induced granulosa cell phospho-Src and phospho-Akt contents and Xiap expression in vitro. The effects of T3 were concentration-dependent, with maximal responses at 1.0 nM. FSH alone decreased Fas Ligand (FasL) content irrespective of the presence of T3. Co-treatment of cell with T3 and FSH decreased Fas content, although neither hormone alone elicited a significant response. Taken together, the present study demonstrates that T3 potentiates the cell survival action of FSH through Src- and PI3K-mediated Xiap up-regulation and decreased Fas and FasL expression.