Abstract: Serotonin (5‐hydroxytryptamine, 5‐HT) was proposed to modulate murine contact allergy by binding to 5‐HT1A/2Areceptors (R). We examined the expression of 5‐HT2CR in the skin of mice with contact allergy, as well as the effects of an agonist and antagonist of this receptor on the elicitation phase of this type of allergy. Immunohistochemistry revealed the presence of 5‐HT2CR on epidermal dendritic cells, and in the inflamed skin the cells expressing this antigen were increased in number (P < 0.01) and exhibited longer dendrites than in the control tissue. Furthermore, the majority of these cells also stained positively for I‐A, a specific marker for Langerhans cells (LCs). Treatment of the skin of sensitized mice in vivo with RO60‐0175 (0.5 and 1.0 mg/kg, once daily for 3 days prior to the challenge with antigen), an agonist for 5‐HT2CR, enhanced the degree of contact eczema (P < 0.05 andP < 0.01 for the two doses respectively), as indicated by ear thickness. This enhancement could be prevented (P < 0.001) by the 5‐HT2CR antagonist SB 242084 at 3 mg/kg. Addition of 5 × 10−5 mol/l RO60‐0175 to murine XS52 cells, which resembles LCs, potentiated their secretion of interleukin (IL)‐1β(P < 0.05); whereas 10−10 mol/l attenuated this secretion (P < 0.05). Under the same conditions, the level of IL‐1βmRNA in these cells (as assessed by RT‐PCR) was unaltered suggesting that this agonist may exert its effect on IL‐1βsecretion at the post‐transcriptional or even at the secretory level. In conclusion, our findings indicate that the 5‐HT2CR is involved in modulating contact allergy in mice.