This study investigated the influence of illness on sexual risk behavior in adolescence and the transition to adulthood, both directly and through moderation of the impact of social disadvantage. We hypothesized positive effects for social disadvantages and illness on sexual risk behavior, consistent with the development of faster life history strategies among young people facing greater life adversity. Using the first two waves of the National Longitudinal Study of Adolescent to Adult Health, we developed a mixed-effects multinomial logistic regression model predicting sexual risk behavior in three comparisons: risky nonmonogamous sex versus safer nonmonogamous sex, versus monogamous sex, and versus being sexually inactive, by social characteristics, illness, interactions thereof, and control covariates. Multiple imputation was used to address a modest amount of missing data. Subjects reporting higher levels of illness had lower odds of having safer nonmonogamous sex (OR = 0.84, p < .001), monogamous sex (OR = 0.82, p < .001), and being sexually inactive (OR = 0.74, p < .001) versus risky nonmonogamous sex, relative to subjects in better health. Illness significantly moderated the sex (OR = 0.88, p < .01), race/ethnicity (e.g., OR = 1.21, p < .001), and childhood SES (OR = 0.94; p < .01) effects for the sexually inactive versus risky nonmonogamous sex comparison. Substantive findings were generally robust across waves and in sensitivity analyses. These findings offer general support for the predictions of life history theory. Illness and various social disadvantages are associated with increased sexual risk behavior in adolescence and the transition to adulthood. Further, analyses indicate that the buffering effects of several protective social statuses against sexual risk-taking are substantially eroded by illness.