Background: Eccrine porocarcinoma (EPC) is a rare skin cancer arising from the intraepidermal sweat duct. EPCs metastasize to regional lymph nodes in approx. 20% of cases with a mortality rate of 67%, due to subsequent distant metastasis. Whereas surgery is effective as first line treatment, optimal management of metastatic porocarcinoma has not yet been defined. Targeting the epidermal growth factor receptor (EGFR) or/and the downstream RAF-MEK-ERK (MAPK) signaling pathway may be a potential treatment for metastatic EPC since EGFR is expressed in more than 81% of skin adnexal tumors. Methods: Immunohistochemical analyses (IHC) of ten primary EPCs and of skin metastases derived from one patient with EPC were performed. EGFR and the downstream signal transduction molecules ERK, p-ERK, AKT and p-AKT were analysed. To study the in vitro effects of EGFR or/and MEK inhibition in EPC, we isolated tumor cells from a skin metastasis of a patient with EPC who was resistant to chemotherapy. Results: All primary tumors and metastases were highly positive for the epidermal growth factor receptor and positive for the signal transduction molecules ERK, p-ERK and AKT but negative for p-AKT. Isolated cutaneous metastatic EPC cells strongly expressed p-EGFR and p-ERK. Treatment of these cells with the anti-EGFR antibody cetuximab or the MEK inhibitor trametinib inhibited tumor growth and moderately induced apoptosis. Moreover, combined EGFR and MEK inhibition significantly enhanced the antiproliferative and proapoptotic effects. This patient underwent surgery for rapidly progressing skin and lymph node metastases and was treated with cetuximab. The patient remained progression-free for 6 months. Conclusions: These data suggest that EPC cells express high levels of EGFR that activates the MAPK pathway thus rendering tumor cells susceptible to EGFR or/and MEK inhibition. Our data provide a strong rationale for targeting EGFR or/and MEK in patients with metastatic EPC.