The tumour promoter phorbol, 12-myristate, 13-acetate (PMA) was shown to inhibit the multiplication of five strains if human epidermal keratinocytes, co-cultivated with 3T3 feeders in the presence of hydrocortisone, cholera toxin and epidermal growth factor. The effect was dose dependent between 10(-9) M and 10(-8) M and this dose response was not affected by omission of any of the tissue culture additives. Experiments performed in 3T3-conditioned medium demonstrated that PMA acted directly on the keratinocytes. Exposure to 10(-8) M PMA for greater than 12 h resulted in a loss of keratinocyte colony-forming efficiency, followed 24-48 h later by altered cell morphology, loss of cell to cell and cell to substratum adhesion and accelerated cytoplasmic and nuclear destruction. PMA-treated keratinocytes also became permeable to Trypan Blue, and many eventually formed cornified envelopes. Other phorbol esters tested produced similar effects to PMA in accordance with their reported tumour promoting activity, although mezerein (a weak tumour promoter) was more potent than PMA. The non-diterpene tumour promoters anthralin and phenobarbital did not have the same effects as PMA. The morphological effects were not produced in other cell types tested consistent with the specific low dose effects of PMA.