Cardiolipin (CL) is found exclusively in the inner mitochondrial membrane. CL deficiency leads to an alteration in the stability of mitochondrial membranes, to an increased permeability as well as a decreased respiratory rate, and therefore to mitochondria which are completely dysfunctional. It is known that reactive oxygen species (ROS) cause a decrease and a variation in CL content, concomitantly the formation of the mitochondrial permeability transition pore facilitates the release of cytochrome c (cyt c) into the cytosol. Melatonin (Mel), the secretory product of the pineal gland, is a potent and efficient endogenous radical scavenger. It has been shown to protect, various biomolecules, such as DNA, membrane lipids, and cytosolic proteins from oxidative damage. To evaluate the protective role of Mel, we have studied U937 cells treated with UV-B irradiation. In our model, the administration of 1mM Mel before UV-B irradiation showed a significant protection from apoptotic cell death, in particular, mitochondrial structure and function were preserved through apoptotic pathways when cells were preincubated with 1mM Mel before UV-B exposure. The cardiolipin-sensitive probe 10-nonyl acridine orange (NAO) was used to monitor changes in mitochondrial lipids. Our data suggest that the Mel treatment protects CL from ROS and this suggests a possible link with the reduction of the apoptotic phenomenon.