Targeted overexpression of an ornithine decarboxylase (ODC) transgene to mouse skin (the K6/ODC mouse) significantly enhances susceptibility to carcinogenesis. While in most strain backgrounds the predominant tumor type resulting from initiation-promotion protocols is benign squamous papilloma, K6/ODC mice on a FVB/N background develop malignant squamous cell carcinomas (SCCs) rapidly and in high multiplicity after carcinogen treatment. We have investigated the utility of polyamine-based therapy against SCCs in this model using the ODC inhibitor 2-difluoromethylornithine delivered orally. At a 2% concentration in drinking water, DFMO caused rapid tumor regression, but in most cases, tumors eventually regrew rapidly even in the presence of DFMO. The tumors that regrew were spindle cell carcinomas, an aggressive undifferentiated variant of SCC. At 1% DFMO in the drinking water, tumors also responded rapidly, but tumor regrowth did not occur. The majority of DFMO-treated SCCs were classified as complete responses, and in some cases, apparent tumor cures were achieved. The enzymatic activity of ODC, the target of DFMO, was substantially reduced after treatment with 1% DFMO and the high SCC polyamine levels, especially putrescine, were also significantly lowered. Based on the results of BrdUrd labeling and TUNEL assays, the effect of DFMO on SCC growth was accompanied by a significant reduction in tumor proliferation with no increase in the apoptotic index. These results demonstrate that SCCs, at least in the mouse, are particularly sensitive to polyamine-based therapy.