Objective To observe the effects of a novel HLA-derived peptide, RDP1258, on the human peripheral blood mononuclear cell (PBMC) proliferation to ConA and MLR, and to investigate the mechanisms. Methods Peptide RDP1258 was chemically synthesized. The effects of the peptide on alloreactive cytotoxic activities of human PBMCs were observed using 3HTdR incorporation method. RDP1258, HLA-B2702.75-84, and control peptide were administrated respectively in every experiment. The activity of heme oxygenase-1 (HO-1) was analyzed by the enzymochemical method. Results The results showed that the synthetic HLA-derived peptide could obviously inhibit the proliferation of human PBMCs and inhibited HO activity in a dose-dependent manner in vitro. Conclusion HO-1 might participate in the inhibitory effect of RDP1258 on the proliferation of human PBMCs induced by mitogen and isoantigen.