Background: Erlotinib has been reported to be associated with a high incidence of skin toxicities, such as acneiform rash, paronychia and xerosis. The aim of this study was to evaluate the efficacy of prophylactic minocycline treatment for the skin toxicities induced by erlotinib, as compared to deferred minocycline treatment. Methods: The study subjects were patients with advanced pancreatic cancer receiving treatment with erlotinib plus gemcitabine. In the prophylactic minocycline group, oral minocycline was administered at the dose of 200 mg/daily during the chemotherapy prior to the emergence of any skin toxicities, while in the deferred minocycline group, oral minocycline treatment at 200mg/daily was initiated after the emergence of grade 2-3 of skin toxicities. In both groups, heparinoids were administered during the chemotherapy and topical steroid therapy was initiated after the emergence of the skin toxicities. Results: A total of 96 patients were enrolled, of which 44 received prophylactic minocycline treatment and 52 received deferred minocycline treatment. The incidence rate of acneiform rash and xerosis of any grade during the first 6 weeks of chemotherapy was significantly reduced in the prophylactic minocycline treatment group as compared with that in the deferred minocycline treatment group (47.7% vs. 80.8%; p<0.001; 2.3% vs. 19.2%; p=0.01); on the other hand, no significant difference in the incidence rate of paronychia of any grade was observed between the two groups. Univariate and multivariate analyses identified prophylactic minocycline treatment and female gender as significant independent factors associated with the incidence of acneiform rash of any grade (odds ratio [OR], 0.20; 95%CI, 0.08 to 0.49; p<0.001; OR, 0.30; 95% CI, 0.11 to 0.87; p=0.03). Conclusions: Prophylactic minocycline treatment significantly reduced the incidence of acneiform rash and xerosis, but not that of paronychia, induced by erlotinib in advanced pancreatic cancer patients. Prophylactic minocycline treatment is recommended for the management of erlotinib-related acneiform rash and xerosis.