Reports of hepatotoxic injury in Vietnam veterans exposed to phenoxy herbicides (mainly, 2,4-D and 2,4,5-T) initiated a retrospective cohort study of veterans self-reporting exposure to Agent Orange (AO) while serving in Vietnam from 1962 to 1971. Historical, medical, and laboratory information was obtained in a subcohort of 100 randomly selected veterans from a pool of 350 registrants. An occupational work exposure ranking system was designed to estimate individual exposure to phenoxy herbicide and its contaminant, dioxin (TCDD). Job classifications were determined by military job codes. Military application of the herbicides used in Vietnam were derived from the National Research Council Report based on the Herbs tapes. Health examination included tests of body systems affected by TCDD and similar agents, e.g., hemopoietic system, cholesterol/lipid metabolism, hepatic function, and skin lesions. Skin rash was utilized as a marker disease, since no case of true chloracne was found among the cohort. The cohort was divided into those with (R) and without (NR) a reported rash during or after the Vietnam tour. The R group had higher frequency (31%) of abnormal liver studies of all types than the NR group (18%). Of the 14 Vietnam veterans with persistent serum transaminase elevations, 86% reported a rash. Abnormal liver functions correlated with herbicide exposure index in both groups, but was more prominent in the R group. Study of the exposure index components showed that the liver abnormalities were related to the months of exposure and not to job classification or exposure rank. Viral hepatitis and alcoholism among both groups accounted for the association between liver abnormalities and cumulative exposure to AO. These data provide strong supportive evidence that chronic liver abnormalities among Vietnam veterans applying to the AO Registry are mainly due to viral or alcoholic causality and not to herbicides and their TCDD contaminant.