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Background: Hyperpigmentation and solar damage remains a difficult problem to treat with topical agents., Aims: To evaluate a novel skin-lightening complex (SLC) comprising four actives targeting melanin formation at multiple levels, namely disodium glycerophosphate, L-leucine, phenylethyl resorcinol, and undecylenoyl phenylalanine, in an oil-in-water emulsion cream., Patients/methods: Skin-lightening complex was evaluated in 80 female subjects of skin types I-III with at least moderate mottled hyperpigmentation. After a wash-out period of 1 month with a sunscreen, the subjects added a cream containing the SLC for 12 weeks twice daily to entire face and continued the sunscreen use., Results: Whereas there was no significant change during the wash-out period, the primary endpoint mottled hyperpigmentation decreased by 32% after the 12-week treatment period with the SLC cream. Secondary endpoints such as severity and number of lentigines, skin tone, and skin brightness also improved. In all, 57% of the subjects showed at least a moderate response, 17% did not improve, and 3% got worse after the treatment., Conclusions: The SLC cream was well tolerated, in particular when comparing with exfoliating or peeling agent containing skin-lightening products. When used with a daily sunscreen, this study confirms that the SLC represents an alternative to hydroquinone, retinoids, and many other skin-lightening actives., (© 2013 Wiley Periodicals, Inc.)