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Herpes simplex virus type 2 (HSV-2) seroprevalence and associated infection risk factors show differences by regions and countries. The aims of the study were to determine the HSV-2 seroprevalence and to evaluate the risk factors for HSV-2 in a national representative survey among adolescents and adults in Mexico.A cross-sectional study was carried out in Mexico on the basis of the National Health and Nutrition Survey 2012, a national representative survey. Demographic, sexual behavior, reproductive health, and lifestyles indicators were considered in the current study. Participants provided biological samples—dried blood spots—to test for HSV-2 antibodies using enzyme-linked immunosorbent assay and Western blot. Bivariate and multivariate analyses were performed to identify variables associated with HSV-2 infections analyzed by sex.National HSV-2 seroprevalence was 9.9%, 2.4% among adolescents and 11.7% among adults with HSV-2 seroprevalence heterogeneous across the country. Women had 12.2% of antibodies against HSV-2 and men had 7.5%. The factors associated with HSV-2 infection among women were age (45–49 years; odds ratio [OR], 19.8), region (southwest; OR, 3.0), urbanization (urban; OR, 1.9), age at sexual debut (≤14 years; OR, 3.4), education level (any; OR, 3.0), and previous abortion (≥2 abortion; OR, 2.1). Among men, age (45–49 years; OR, 11.7), region (southwest; OR, 3.0), urbanization (urban, odds ratio [OR], 1.7), and HIV care (OR, 7.1) were associated with the infection.Approximately 10% of Mexicans aged 15 to 49 years had HSV-2 antibodies, with differences by sex, region, education level, urbanization, HIV care, and childbirth, highlighting the relevance of health inequalities in the country: social inequalities seem to matter in terms of the probability of HSV-2 infections.