We studied whether 16,16-dimethyl prostaglandin E₂ (dmPGE₂) may prevent acute liver damage induced by carbon tetrachloride (CCl₄) in the rat. One hundred thirty male rats were divided into the following groups: (1) controls, (2) rats given CCl₄ 6670 mg/kg body wt subcutaneously, (3) rats pretreated with 5 µg/kg dmPGE₂ given subcutaneously 30 min before, and 8 and 24 h after CCl₄ administration, and (4) animals given dmPGE₂ only as in group 3. Liver damage was assessed by biochemical studies (SGPT, serum alkaline phosphatase, and bilirubin) and by histology. In rats receiving CCl₄, alone, SGPT activities were significantly elevated to 1024 ± 82 U/L, 1270 ± 120 U/L, 386 ± 48 U/L and 208 ± 20 U/L at 24, 48, 96, and 120 h after CCl₄ respectively. In animals pretreated with dmPGE₂ before CCl₄, SGPT activities were 201 ± 24 U/L, 55 ± 4.6 U/L, 28 ± 4 U/L, and 24 ± 3 U/L at 24, 48, 96, and 120 h after CCl₄, respectively (p < 0.01, versus animals receiving CCl₄ only). Histologically, livers of rats treated with CCl₄, alone showed severe centrilobular necrosis at 24 and 48 h. Livers of animals pretreated with dmPGE₂ before CCl₄, did not show necrosis. It is concluded that dmPGE₂ protects the liver against cell necrosis induced by CCl₄ in the rat.