Anandamide (AEA), a prominent member of the endogenous ligands of cannabinoid receptors (endocannabinoids), is known to adversely affect female fertility. However, a potential role of AEA in male reproductive functions is unknown. Here we report evidence that immature mouse Sertoli cells have the biochemical tools to bind and inactivate AEA, i.e. a functional type-2 cannabinoid receptor (CB2R), a selective AEA membrane transporter, and an AEA-degrading enzyme fatty acid amide hydrolase. We show that, unlike CB2R, the activity of AEA membrane transporter and the activity and expression of FAAH decrease, whereas the apoptosis-inducing activity of AEA increases with age during the neonatal period. We also show that FSH reduces the apoptotic potential of AEA, but not that of its nonhydrolyzable analog methanandamide. Concomitantly, FSH enhances FAAH activity in a manner dependent on mRNA transcription and protein synthesis and apparently involving cAMP. These data demonstrate that Sertoli cells partake in the peripheral endocannabinoid system, and that FSH reduces the apoptotic potential of AEA by activating FAAH. Taken together, it can be suggested that the endocannabinoid network plays a role in the hormonal regulation of male fertility.