Hypericum perforatum (St John’s wort) is widely used as a treatment for depression. A phototoxic reaction, due to its content of hypericin, can occur in animals and in cell culture, and has been reported in humans. Hypericin displays absorption within the ultraviolet (UV) A1 spectrum and there may therefore be a potential for phototoxicity if taken during high-dose UVA1 therapy. The phototoxicity risk of H. perforatum ingestion was assessed in 11 volunteers of skin types I and II exposed to a geometric dose series of UVA1 irradiation from a high-output source on the photoprotected lower back skin at eight 1.5-cm test areas. Irradiation was carried out at baseline and after 10 days of H. perforatum extract 1020 mg daily. Four, 8, 24 and 48 h after each exposure, the minimal erythema dose (MED) and the presence or absence of pigmentation were recorded visually and erythema was assessed objectively with an erythema meter. The median MED and D(0.025), an objective measure of MED, were lower at all time-points after H. perforatum ingestion. The visual erythemal peak (lowest median MED), which was seen at 8 h post-irradiation, was lower after H. perforatum (median 14 J/cm², range 10–56) than at baseline (median 20 J/cm², range 14–56). Similarly, the median D(0.025) at 8 h post-irradiation was lower after H. perforatum (median 22.0 J/cm², range 15.2–53.9) than at baseline (median 33.7 J/cm², range 22.9–136.0). The MED and D(0.025) were also significantly different at the 48-h and 4-h time-points, respectively. Significance was not reached at the 24-h time-point. Median intensity of post-irradiation erythema increased at all time-points after ingestion of H. perforatum. Despite these differences, the maximum slope of the dose–response curve was not increased after H. perforatum ingestion.