The ability of subcutaneous 16,16-dimethyl PGE2 to protect the liver and the kidney against damage induced by carbon tetrachloride and ANIT (alpha-napthylisothiocyanate) was examined. Rats were given 5-75 micrograms/kg of 16,16-dimethyl PGE2 24 and 0.5 hrs before challenge with 1 ml of oral carbon tetrachloride with an additional prostaglandin dose 6 hrs later. Twenty-four hrs after carbon tetrachloride animals was sacrificed by decapitation. 16,16-Dimethyl PGE2 partially prevented fat accumulation and necrosis in the liver with complete or partial reduction in the SGPT caused by the hepatotoxin. Higher doses of carbon tetrachloride (1.5 ml) caused elevation in BUN and uric acid also; these changes were prevented by 16,16-dimethyl PGE2 even when doses of the prostaglandin were too low to protect against liver necrosis. Elevated serum bilirubin observed 48 hrs after oral ANIT (30 mg/kg) was prevented by 100 micrograms/kg of 16,16-dimethyl PGE2 given 24 and 0.5 hrs prior to the challenge with additional doses 6 and 24 hrs after ANIT. Higher doses of oral ANIT (200 mg/kg) when combined with small doses of carbon tetrachloride (0.25 ml per rat) resulted in elevated BUN and uric acid levels in the serum although neither compound produced these changes when given alone. 16,16-Dimethyl PGE2 (75 micrograms/kg) administered by the same schedule as used for protection against ANIT resulted in normalization of these parameters in the absence of significant liver protection. Thus, it appears that 16,16-dimethyl PGE2 can protect the liver against necrosis induced by moderate amounts of carbon tetrachloride and ANIT. At higher doses of these hepatotoxins, the liver is not protected by prostaglandins. Elevation of BUN and uric acid is observed under these conditions, however, and can be prevented by 16,16-dimethyl PGE2.