Although case reports of herpes simplex virus (HSV) causing acute hepatitis in otherwise healthy adults have appeared recently in the literature, a prospective study of the incidence of HSV-hepatitis in the general population hitherto has not been reported. In the present study, serum samples from 124 young adults attending a sexually transmitted disease clinic with either genital herpes infections (n = 86) or non-herpes sexually transmitted diseases (n = 38) (controls) were analyzed for liver enzyme abnormalities (including aspartate aminotransferase [AST] and alanine aminotransferase [ALT]). Twelve of eighty-six (14%) herpes-infected patients had mildly abnormal liver enzyme tests (less than or equal to twice the upper limit of normal) as opposed to only 1 of 38 controls (2.6%), (P less than .05). All individuals in the herpes-hepatitis group were anicteric, and only two complained of constitutional symptoms (malaise and fatigue). Liver enzyme tests were repeated in nine herpes-hepatitis patients 1 week after their genital lesions had resolved, and in six of nine patients the results had returned to within normal limits. Four patients subsequently returned at the onset of a recurrence of their genital herpes. In all four, serum ALT levels were elevated from the previous occasion, and in three of the four levels just exceeded the upper limit of normal. One patient was followed through three recurrences of his genital herpes. In that individual, the extent of liver enzyme abnormalities appeared to correlate with the presence or absence of his genital lesions.(ABSTRACT TRUNCATED AT 250 WORDS)