C225 is an antibody to the epidermal growth factor receptor (EGFR), and inhibits growth of various tumour cells. The antibody is currently being used as a therapeutic agent in several clinical trials of patients with carcinomas. Objectives To determine and investigate the cutaneous side-effects in cancer patients treated with C225. Methods We clinically examined 10 patients treated with C225, and performed immunohistochemical and in situ hybridization studies on skin biopsies. Results The most common cutaneous reaction to C225 therapy was the development of an acneiform follicular eruption, which was most pronounced on the face, chest and upper back and typically manifested a week after the onset of treatment. The consistency of the morphology and timing of the clinical findings in 10 different patients following monotherapy with C225 strongly suggested a direct biological effect of the antibody. Additional dermatological side-effects included focal areas of tender paronychial inflammation of toes and fingers and small aphthous ulcers of the oral mucosa. Serial punch biopsies of chest skin before and after treatment (at 8 days) revealed two main reaction patterns: a superficial dermal inflammatory cell infiltrate surrounding hyperkeratotic and ectatic follicular infundibula, and a suppurative superficial folliculitis. In two biopsies focal intraepidermal acantholysis was found. Microbiological cultures failed to reveal an infectious aetiology. Immunohistochemical and in situ hybridization studies on a subset of the biopsies showed an increase in the expression of p27Kip1 in epidermal keratinocytes after treatment with C225. Conclusions Our findings support the concept that p27Kip1 plays a part in the in vivo regulation of follicular and epidermal homeostasis by EGFR.