Seroprevalence of and coinfection with herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) in the United States were analyzed by use of data from a nationally representative survey (National Health and Nutrition Examination Survey III, 1988–1994). Evidence was explored for possible protection by prior HSV-1 infection against infection and clinical disease with HSV-2. Overall, 27.1% of persons aged ≥12 years were seronegative for HSV-1 and HSV-2; 51.0% were seropositive for HSV-1 only, 5.3% for HSV-2 only, and 16.6% for both HSV-1 and HSV-2. The seroprevalence of HSV-2 was higher in persons with HSV-1 antibody. Approximately 76% of persons who had HSV-2 antibody also had HSV-1 antibody. Persons seropositive for HSV-2 only reported a history of genital herpes more frequently (16.2 %) than persons seropositive for both HSV-1 and HSV-2 (5.9 %). The seroprevalence of HSV-1 and age at infection may influence the epidemiology of clinical genital herpes, even if prior HSV-1 infection does not prevent HSV-2 infection.