The effect of a low-fat diet on occurrence of non-melanoma skin cancer was examined in a 2-year dietary intervention trial. A total of 101 skin-cancer patients were randomized either to a control group that consumed, on average, 38% of caloric intake as fat, and in which no changes in dietary habits were introduced, or to a low-fat dietary-intervention group, in which patients were instructed to limit their calories from fat to 20% of total caloric intake. Patients were examined at 4-month intervals by dermatologists blinded to their dietary assignments. Nutrient analyses, conducted at each of the 4-month follow-up visits, indicated that the % calories of fat consumed in the intervention group had been reduced to 21% at 4 months and remained below this level throughout the 2-year period. There were no significant differences in total calories consumed, or in mean body weights, between the control and the intervention groups. Nor were there significant group differences in P/S ratios until month 24. Numbers of new skin cancers treated at each examination were analyzed in 8-month periods of the 2-year study. Comparisons of skin-cancer occurrences revealed no significant changes in the control group from baseline values. However, cancer occurrence in the low-fat intervention group declined after the first 8-month period and reached statistical significance by the last 8-month period. Patients in this group had significantly fewer cancers in the last 8-month period than did patients in the control group. In addition, there was a significant reduction in the number of patients developing skin cancer in the last 8-month period, as compared with the first 8-month period, within the low-fat intervention group. There were no significant changes in the control group. These data indicate that a low-fat diet can significantly reduce occurrence of a highly prevalent form of cancer.