Background: The use of herbal supplements is common, yet little is known about their pharmacologic properties. The purpose of this study was to assess the effects of 23 commonly used herbal supplements on histamine skin prick testing (SPT). Methods: Fifteen healthy volunteers participated in a double-blind, placebo-controlled, single-dose, crossover study. Wheal and flare responses to SPT with histamine phosphate (1 mg/ml) were measured before and 4 h after administration of each of the 23 popular herbal supplements, fexofenadine (60 mg) and placebo. Wheal and flare areas were recorded with tracings performed 10 min after the prick test and measured with a PC-digitizer using stereometric software. Results: Fexofenadine significantly suppressed the wheal (P < 0.001) and flare (P = 0.02) areas compared with placebo. None of the herbal supplements caused significant suppression of the wheal and flare areas compared with placebo (P > 0.10). Conclusion: When taken in single-doses, the popular herbal supplements tested did not significantly affect the histamine skin response. Therefore, it seems unnecessary for clinicians to ask patients to discontinue these herbal supplements prior to allergy skin testing.