The ability to modify skin injury due to ultraviolet light (UVB) by the nonsteroidal anti-inflammatory drugs (NSAIDs) oral ibuprofen (IB) or indomethacin (IN) plus topical betamethasone dipropionate (BD) was studied in 24 subjects in this open-label, four-way, cross-over trial. All subjects received UVB at weekly intervals: group 1 was randomized to IB, BD, IB + BD or control, and group 2 to IN, BD, IN + BD or control. Oral medications were given prior to and after exposure to UVB, but BD was applied only afterwards. The skin response to UVB [erythema and increased skin blood flow (SBF)] was measured serially for 96 h. A skin biopsy was taken at 24 h after each dosing with UVB. At maximum erythema (8-12 h after UVB), the following approximate reductions in SBF (compared to control responses) were noted: 42-58% for combination therapies, 33-40% for IB or IN alone, and 17% for BD alone. SBF tended to equalize across all treatments by 24 h and remained until 96 h. Skin biopsy results were consistent with the noninvasive findings. Thus, we observed a synergistic effect of reduction of UVB-induced erythema and SBF with combinations of oral NSAIDs and topical corticosteroids. This study could have implications for the therapy of sunburn in humans.