Peptides derived from the heavy chain of the HLA Class-I molecules have been shown to modulate immune responses both in vivo and in vitro. Using a computer-aided rational drug design approach, novel immunomodulatory peptides were designed based on peptide 2702.75–85, derived from HLA-B2702. Several peptides were identified which had increased immunomodulatory activity, including peptides RDP1258 and its d-isomer the peptide Allotrap 1258. The present study using Skh/hr hairless mouse skin model evaluated the in vivo effects of Allotrap 1258 on acute UVB-induced skin inflammation. Here we demonstrate that intraperitoneal administration of Allotrap 1258 1 h prior to UV exposure resulted in significantly diminished levels of UV-induced tumor necrosis factor (TNF)-α protein production in the epidermis but had no effect on other parameters of the acute UV-induced inflammatory response. By virtue of its ability to suppress TNF-α protein production, Allotrap 1258 could prove to be an effective modulator of inflammatory responses.