In vivo administration in mice of a synthetic analog of prostaglandin E2 (PGE2) caused a selective and dramatic decrease of CD4+CD8+ double-positive, CD3/T-cell-receptor-αb10 cells in the thymus. This loss was corticosteroid-independent and not affected by Cyclosporin A. The disappearance of CD4+CD8+ thymocytes was strictly correlated with the induction of apoptosis inside the thymus as shown by morphological studies and by the induction of intracellular transglutaminase expression. Considering that PGE2 has been found to be produced by different cell populations inside the thymus, these results indicate that PGE2 may act as endogenous signals for apoptosis during T-cell differentiation.