When lead in car fuel was removed in the United States beginning from 1979, it was replaced with methyl tertiary-butyl ether (MTBE). This move came as a result of the discovery of the deleterious effects of lead on health and the environment. As of January 2001, leaded car fuel in Saudi Arabia was also replaced with MTBE, at a concentration of 12 - 15%. MTBE dissolves readily in water and evaporates quickly. This study focused on the possible health toxicity of MTBE in drinking water, as manifested by changes in the activities of certain plasma enzymes, such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), Y-glutamyltransferase (GGT), lactate dehydrogenase (LDH), and creatine kinase (CK). One hundred and twenty male Wistar rats were exposed to five different MTBE concentrations (0.0, 1,000, 1,500, 2,000, and 2,500 ppm) for 60 days. The results showed increased levels (U/I) of ALT at all MTBE concentrations by 48.8, 19.2, 16.9, and 15.4%, respectively. The AST concentration (U/I) increased significantly (29.2%) only at 2,000 ppm MTBE. This significant increase of blood plasma enzymes, which are related to liver function, may indicate injury or damage to liver cells. However, there were no significant differences between the MTBE concentrations in ALP, GGT, LDH or CK and AST. This may indicate there was no marked potentiating acute liver damage induced by MTBE.