The pineal hormone melatonin (Mel), in addition to having a well-established role as a regulator of circadian rhythms, modulates nonneural compartments by acting on specific plasma membrane receptors (MT1/MT2) present in many different cell types. Mel plays immunomodulatory roles and is an oncostatic and antiproliferative agent; this led to the widespread belief that Mel may induce or potentiate apoptosis on tumor cells, even though no clear indications have been presented so far. Here we report that Mel is not apoptogenic on U937 human monocytic cells, which are known to possess MT1 receptors at the times (up to 48 h) and doses (up to 1 mM) tested. Mel does not even potentiate apoptosis, but instead, significantly reduces apoptosis induced by both cell-damaging agents (intrinsic pathway) and physiological means (extrinsic pathway). The doses required for the antiapoptotic effect (>or=100 microM) are apparently not compatible with receptor stimulation (receptor affinity<1 nM). However, receptor involvement cannot be ruled out, because we discovered that the actual Mel concentration active on cells was lower than the nominal one because of sequestration by fetal calf serum (FCS). Accordingly, in FCS-free conditions, Mel doses required for a significant antiapoptotic effect are much lower.