ABSTRACT It is well documented that l-carnitine (L-C) has protective effects against various types of injury. Although its antioxidant action has been reported as a major mechanism, other suggested pathways may be implicated in its protective effect. This study was designed to evaluate the suggested pathways which may be implicated in the protective effect of L-C on liver injury caused by cyclosporine A (CsA). Forty-two adult male Swiss albino rats weighing 180–200 g were assigned randomly into 6 groups, 7 rats each: rats were given i.p. either sterile saline (1 ml/kg/d), L-C (50 or 200 mg/kg/d), CsA (15 mg/kg/d), or a combination of CsA and L-C for 4 weeks. The impact of L-C on the hepatic injury was assessed by estimation of serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and total bilirubin (T.Bil). Superoxide dismutase (SOD), glutathione reductase (GSH-Rd), malondialdehyde (MDA) levels were measured in both serum and liver homogenates. In addition, prostaglandin E2 (PGE2) and nitric oxide (NO) were estimated in liver homogenates. CsA treatment caused liver dysfunction, manifested by elevation in serum AST, ALT, and T.Bil levels, and associated with elevation in MDA and reduction in SOD, GSH-Rd, PGE2, and NO levels in serum and liver homogenates. Concomitant administration of L-C induced dose-dependent improvement of liver functions, antioxidant enzymes, and MDA levels. Furthermore, the administration of L-C at a high dose ameliorated the hepatic levels of PGE2 and NO. These findings suggest that L-C has a protective effect against CsA-induced liver injury not only by its antioxidant properties but also, by its effect on PGE2 and NO pathways