BACKGROUND: Cutaneous pigmented lesions urge the need to find safe and effective treatments to lighten the skin. OBJECTIVE: The aim of this study was to combine a retinoid (retinaldehyde), a new phenolic agent (4-(1-phenylethyl)-resorcinol) and a proreducing agent (delta-tocopheryl-beta-D-glucopyranoside) to achieve synergistic actions for skin lightening. METHODS: The tolerance profile and the depigmenting properties of these agents were assessed in murine keratinocyte and melanocyte cell lines, as well as in a 3-dimensional model of reconstructed epidermis. RESULTS: Retinaldehyde and 4-(1-phenylethyl)-resorcinol induced a significant decrease of tissue viability in reconstructed epidermis, but this cytotoxicity was prevented by the addition of delta-tocopheryl-beta-D-glucopyranoside. The combination of the three agents was, however, efficient in decreasing the specific melanin content and the density of active melanocytes. CONCLUSION: A combination of various chemicals acting via different mechanisms allows a decrease in the toxicity of each compound alone while retaining optimal skin-lightening properties.