Background: Tea tree oil is the essential oil steam-distilled from Melaleuca alternifolia, an Australian native plant. In recent years it has become increasingly popular as an antimicrobial for the treatment of conditions such as tinea pedis and acne. Objectives: To investigate the anti-inflammatory properties of tea tree oil on histamine-induced weal and flare. Methods: Twenty-seven volunteers were injected intradermally in each forearm (study and control assigned on an alternating basis) with histamine diphosphate (5 μg in 50 μL). Flare and weal diameters and double skin thickness were measured every 10 min for 1 h to calculate flare area and weal volume. At 20 min, 25 μL of 100% tea tree oil was applied topically to the study forearm of 21 volunteers. For six volunteers, 25 μL paraffin oil was applied instead of tea tree oil. Results: Application of liquid paraffin had no significant effect on histamine-induced weal and flare. There was also no difference in mean flare area between control arms and those on which tea tree oil was applied. However, mean weal volume significantly decreased after tea tree oil application (10 min after tea tree oil application, P = 0.0004, Mann-Whitney U-test). Conclusions: This is the first study to show experimentally that tea tree oil can reduce histamine-induced skin inflammation.