Repetitive topical applications of 2 micrograms 12-O-tetradecanoylphorbol-13-acetate (TPA) twice weekly for 37 to 52 weeks induced a sustained epidermal hyperplasia, hyperplasia of hair follicles, and increased dermal cellularity in SENCAR mice. In addition, after 52 weeks of protracted promoter treatment most animals developed generalized amyloidosis involving liver and spleen, as well as interstitial nephritis. Severe pyelonephritis and papillary necrosis were also frequently seen. Reactive lymphoid hyperplasia was also a frequent finding. Chronic administration of TPA is not an innocuous treatment affecting only the interfollicular epidermis. The general effect of the promoter on the animals was a marked decrease in their longevity, probably through impairment of the immune system.