Promotion of tumors in mouse skin by 12-O-tetradecanoylphorbol-13-acetate (TPA) was reduced by treatment with either 1-phenyl-2-(p-hydroxyphenyl)-3,5- dioxo-4-n-butylpyrazolidine monohydrate (oxyphenbutazone) or 7-chloro-3,3a-dihydro-2H,9H-isoxazolo(3,2-b) (1,3)benzoxazin-9-one (W2354) (Slaga TJ, Scribner J D: J Natl Cancer Inst 51:1723-1725, 1973). Although oxyphenbutazone significantly reduced TPA-induced incorporation of tritiated precursors into cellular macromolecules, W2354 appeared to have a minimal effect on such incorporation. Similarly, oxyphenbutazone reduced TPA-induced enhancement of a specific protein in mouse epidermal cytosol to approximately control levels, but W2354 had no effect on this protein response. Neither compound affected gross inflammation produced by TPA, although oxyphenbutazone reduced histologically determined hyperplasia. The significance of selective protein induction in mouse epidermal cytosol as a marker for an effective promoter was further investigated by the determination of whether either acetic acid (inflammatory, hyperplasiogenic, but nonpromoting) or 3'methylcholanthrene (an efficient initiator) would produce the same protein induction found after TPA treatment. Neither produced a significant deviation from that found in untreated mice. It thus appears that a multitude of events contributes to effective tumor promotion, that inflammation and simple hyperplasia are inadequate for promotion, but that suppression of either inflammation or hyperplasia or TPA-induced alteration of genetic expression will result in some loss of promoting efficiency.