Dithranol is one of the most effective topical medications for treating plaque psoriasis. However, its clinical use is limited by irritative adverse reactions to the skin, such as oedema, erythema, and pruritus, caused by poorly understood mechanisms. Because TRPV1 activation mediates skin irritation caused by several drugs, we conducted blind and randomised experiments in male and female C57BL/6 mice to elucidate the role of TRPV1 in dithranol-induced irritation. Dithranol (0.01%-0.5%) or vehicle was applied topically to the right ear of the animals. Oedema, erythema, and pruritus were monitored from 2 h to 6 days after application. Treatment with 0.5% dithranol caused oedema and erythema, but not pruritus, starting at 6 h, reaching its highest point at 1 day, and persisting up to 6 days after treatment, mainly in male mice. The 0.1% dose induced erythema but not oedema. Interestingly, topical application of 1% capsaicin was shown to defunctionalise TRPV1-positive fibres and did not influence early irritation caused by dithranol (2 h-2 days). However, it increased the late phase of irritation (5-6 days). Similarly, salicylate did not reduce the early irritation caused by dithranol but also increased the late phase. Antagonism by SB366791 and 4-tert-butylcyclohexanol did not alter skin irritation. Our results suggest that, contrary to our initial hypothesis, TRPV1 appears to act protectively against skin irritation caused by dithranol, particularly in the late stage.