Wistar rats were fed a diet deficient in essential fatty acids (EFA). Control animals received the same diet to which was added 5% corn oil, a source of EFA. The experimental group showed clinical and chromatographic evidences of EFA deficiency. Groups of deficient and control animals were killed at various periods up to 100 weeks of age. Of 43 EFA-deficient rats, 8 (18.6%) had papillary transitional cell tumors of the urinary tract. None of the 36 controls had tumors (P less than 0.01). In 7 animals, tumors were found in the renal pelvis and upper portion of the ureter; in one, the tumor was in the bladder. The tumors were more frequent at the end of the first year of life and after the first year of life, with no significant sex differences. Tumors showed various degrees of differentiation and a trend toward bilateral involvement. Subepithelial and muscle invasion of tumor was noted in 5 rats. Most tumors were polycentric, and carcinomas in situ were seen. Atypical hyperplasias were found in 35% of the EFA-deficient rats and in 3% of the controls. Typical hyperplasias were seen in 63% of the EFA-deficient rats and in 72% of the controls, Renal calcifications, congestion, inflammation, and hydronephrosis were also seen. No significant differences other than congestion were found in both groups. Our results suggest that the mechanisms regulating proliferation of urothelial cells are upset in EFA-deficient rats; this favors the appearance of atypical hyperplasias and tumors. Therefore, EFA deficiency in the rat may be a useful model for the study of the causes and pathogenesis of human urothelial cancer.