A mucocutaneous reaction in mice associated with Doxil® treatment was identified as auricular erythema (AE). Given that the immuno-targeting of Doxil® to tumors was found to influence also its systemic biodistribution pattern, the attempt was made to exploit a specific targeting of Doxil® to reduce the manifestation of this adverse reaction. This problem is of general significance, since cutaneous reactions often lead to alterations of Doxil® dosing regimen in patients and might subsequently compromise the therapeutic outcome of cancer treatment. Tumor-bearing mice were used to study the biodistribution and skin–tissue accumulation effects of the tumor-targeted Doxil® (the clinically used anti-cancer formulation) coupled with the anti-cancer monoclonal 2C5 antibody (mAb 2C5) as well as AE caused by Doxil® application. The modification of Doxil® with mAb 2C5 resulted in a significant decrease in the normal skin accumulation of doxorubicin compared to original Doxil® and substantially reduced AE. The frequency of AE was decreased by three to fourfold with the mAb 2C5-modified doxorubicin-loaded long-circulating liposomes. Thus, targeting of Doxil® with the anti-cancer mAb 2C5 not only can increase the tumor-specific accumulation of the drug, but also diminishes the cutaneous side effect of the original Doxil® therapy.