The effect of SM12502 and CV6209, platelet-activating factor (PAF) receptor antagonists on corticosterone (B) secretion induced by ACTH was examined in the perfused adrenals of CD1 ICR (normal) and CD1 ICR nu/nu (athymic) mice. Bilateral adrenals were perfused in situ with an artificial medium equilibrated by 95% O₂ + 5% CO₂. Continuous infusion of 10 μM SM12502 or CV6209 inhibited the B response to 100 pg/ml ACTH markedly in normal mice but insignificantly in athymic mice. Infusion of PAF did not significantly affect B secretion in either normal or athymic mice. Administration of 0.1 μM of N-methylcarbamyl PAF, a nonmetabolizable PAF agonist, significantly increased B secretion in normal mice, but not in athymic mice. Infusion of SM12502 significantly depressed the B response to 10 μM forskolin or 1 mM dibutyryl cyclicAMP (cAMP) in normal mice, but not in athymic mice. The results indicate that endogenous PAF and its receptor may play a role in the ACTH-initiated signaling pathway at the phase after responsiveness to cAMP and its receptor may have little function in athymic mice.