Thioredoxin-1 is a low molecular weight redox protein that protects cells against oxidant damage. Thioredoxin-1 levels are increased in the epidermal layer of sun-damaged human skin. Thioredoxin-1 levels are also increased in several human primary tumors where its expression is associated with increased tumor cell proliferation, decreased apoptosis and aggressive tumor growth. We have investigated whether increased thioredoxin-1 levels in skin can lead to increased tumor formation using transgenic mice with mouse thioredoxin-1 expressed in keratinocytes under the control of the keratinocyte-14 (K14) promoter. Thioredoxin-1 protein expression was increased 2-fold in the keratinocyte layer of the transgenic mice. The skin was macroscopically and histologically normal but in the two-stage model of carcinogenesis using topical dimethylbenzanthracene (DMBA) as an initiator and 12-O-tetradecanoylphorbol-13-acetate (TPA) as a promoting agent, there was a 6-fold increase in the number of papillomas per mouse and a 3-fold increase in papilloma size in the K14 thioredoxin-1 transgenic mice compared with non-transgenic littermates. Thus, increased thioredoxin-1 in keratinocytes acts as an enhancer of carcinogenesis in the DMBA/TPA two-stage model of skin carcinogenesis in mice.