Skin cancers such as squamous cell carcinoma (SCC) are among the most aggressive types of tumors. They come with a high rate of growth, metastasis, and frequently occurring chemoresistance. Smoking is one of the risk factors for SCC progression, and the α7 nicotinic acetylcholine receptor (α7-nAChR) is a promising target for SCC therapy. Human secreted protein SLURP-1 is an auto/paracrine regulator of epithelial homeostasis and a selective negative allosteric modulator of α7-nAChR. Recently, we demonstrated the high efficiency of the therapy based on the recombinant SLURP-1 in controlling SCC cell growth and metastasis . The anti-tumor effect of SLURP-1 was mediated through interaction with both α7-nAChR and the epidermal growth factor receptor (EGFR). Cytotoxic antibiotic doxorubicin has been proposed for the SCC therapy; however, its use is limited due to the high toxicity. In this study we investigated the use of an enhanced SLURP-1 dose and of a combination of SLURP-1 with low-dozen doxorubicin for SCC treatment of mice xenografted with squamous cell carcinoma A431 cells. An increased SLURP-1 dose didn't significantly enhance the efficiency of the therapy. However, the combination with doxorubicin further enhanced the anti- tumor activity of SLURP-1 and dramatically suppressed metastasis. The effect from the combined therapy was accompanied by down-regulation of EGFR expression in tumors. Direct inhibition of EGFR activation by SLURP-1 was shown. No toxicity of the combined therapy was encountered. Our data indicate that the combination of SLURP-1 with chemotherapy in lower doses is a promising approach in SCC treatment and should be further studied.