Psoralen plus ultraviolet A (PUVA), utilizing oral 8-methoxypsoralen (8-MOP), is a widely utilized and effective treatment for psoriasis vulgaris. Previous studies have suggested that PUVA's mechanism of action in psoriasis is a result of its direct lymphotoxic effects. Trimethylpsoralen (TMP), a potentially safer compound, has been found to be effective in psoriasis during bath water delivery. In this study we examined the relative antilymphocytic effects of TMP and 8-MOP through both flow cytometry and tissue analysis on lesional skin during clinical treatment. Based on FACS analysis on phytohemagglutinin-activated lymphocytes, we found TMP to be nearly 10,000 fold more lymphotoxic compared to 8-MOP. In addition, lymphocytes treated with 8-MOP or TMP with UVA displayed DNA degradation patterns typical of apoptotic cell death. These findings were consistent with our investigation of treated psoriatic skin, with virtual elimination of epidermal CD3+ T-cells following bath water treatment with TMP or 8-MOP. These results support the theory that the therapeutic effects of PUVA stem from its toxic effects on activated lymphocytes. If further investigation supports TMP's lack of carcinogenicity, this potent lymphotoxic treatment may prove to be one of the safest and most effective treatments for psoriasis.