An increasing incidence of human skin cancer and other adverse effects of solar ultraviolet (UV) radiation enhance the need for novel chemoprevention strategies. Here, we have studied the effect of silibinin on UVB-induced apoptosis in HaCaT cells. Silibinin strongly prevented lower doses (15 and 30 mJ/cm2) of UVB-induced apoptosis, as observed by a reversal in UVB-caused poly(ADP-ribose) polymerase (PARP) cleavage, caspase 9 activation and an increase in apoptotic cells. UVB-induced PARP cleavage was also abolished by all caspase inhibitor, suggesting that it is a caspase-dependent effect. In other studies, silibinin restored UVB-caused depletion of a protein inhibitor of apoptosis, survivin, concomitant with up-regulation of transcription factor nuclear factor kappaB DNA binding activity, without any noticeable effect on UVB-caused activated protein-1 activation. Further, silibinin treatment up-regulated UVB-induced extracellular signal regulated kinase 1/2 phosphorylation, suggesting a possible role as a survival event in the protective effect of silibinin. In other studies, silibinin caused a moderate increase in phospho-Bcl-2, without any noticeable changes in total Bcl-2 levels, and down-regulated bax levels moderately. Silibinin also caused a strong decrease in Bad heterodimerization with Bclx(L), which was consistent with an increased translocation of Bclx(L) to the mitochondria from the cytosol. Consistent with its protective effect on UVB-caused apoptosis, silibinin also increased S phase arrest, possibly providing a prolonged time for efficient DNA repair. Interestingly, the protective effects of silibinin in HaCaT cells were lost at a higher dose of UVB (120 mJ/cm2) and instead it further enhanced UVB-caused apoptosis together with a strong decrease in UVB-caused activated protein-1 activation. Together, these results clearly demonstrate the dual efficacy of silibinin in protecting or enhancing UVB-caused apoptosis in the same cellular system and suggest that silibinin possibly works as a UVB damage sensor to exert its biological action.