The phototherapeutic properties and tissue distribution of hypericin were investigated in DBA/2 mice bearing subcutaneously transplanted P388 lymphoma cells. The efficacy of the photodynamic therapy (PDT) 2 h after administration of hypericin (2, 5, or 20 mg/kg, i.p., 120 J/cm2, 595 nm) was substantially greater than the efficacy after a 24 h interval. PDT with Photofrin (5 mg/kg, i.p., 24-h interval, 120 J/cm2, 630 nm) showed no significant antitumoral effect. The hypericin uptake in some tissues was measured after administration of hypericin (5 or 20 mg/kg, i.p.) up to 168 h. A comparison of the distribution data and the PDT efficacy at various intervals suggests that the plasma concentration of hypericin, and to a lesser extent the tumor uptake, determines the tumor response to PDT with hypericin.