The tumor-producing and skin-irritating activity of the antipsoriatic drug dithranol and its 10-acyl analogues butantrone (10-butyryl dithranol), 10-isobutyryl dithranol and 10-valeryl dithranol were studied in 650 SENCAR mice using a two-stage skin carcinogenesis assay. An initiation with 20 micrograms of 7,12-dimethylbenz(alpha)anthracene (DMBA) was followed 2 weeks later by three applications per week of the test compounds in 50 microliter of acetone for 21 weeks. In addition the compounds were studied without DMBA pre-treatment using application periods of 21 and 36 weeks. The concentration of dithranol was the maximum tolerated, 3.5 mM. For the less irritating 10-acyl analogues 30 mM solutions were used. The first signs of skin irritation were observed after an application period of 1-2 weeks and the irritation continued to the end of the experiment in all groups except the acetone controls. Dithranol caused the most severe irritation although the differences between the groups were not pronounced. On histopathology, the majority of animals had hyperplasia and other inflammatory changes of the skin. The first papillomas appeared 8-11 weeks after initiation and the incidences of papillomas at the end of the experiment were 85% (dithranol 3.5 mM), 16% (butantrone 30 mM), 36% (10-isobutyryl dithranol 30 mM) and 50% (10-valeryl dithranol 30 mM). Without initiation the incidences were 6 and 2% (dithranol), 2 and 2% (butantrone) and 2 and 0% (10-valeryl dithranol) in the 21- and 36-week studies, respectively. Histologically, the papillomas were mostly squamous papillomas and only a few keratoacanthomas were found. It is concluded that the tumor-producing and skin-irritating activity of dithranol is clearly greater than that of butantrone, 10-isobutyryl dithranol and 10-valeryl dithranol.