We dissected associations between initiation and intensity of substance use and number of sexual partners using pooled data from high school seniors (weighted n = 13,580) who participated in the 1999-2007 Youth Risk Behavior Surveillance System (YRBS), a cross-sectional, nationally representative survey. In multinomial multivariable logistic regressions, number of sexual partners steadily increased as substance use intensified from never use to experimental/new user to heavy use across all substances for both male and females. Severity of substance use is more closely related to, and thus a better indicator of, higher number of sexual partners than age of substance use onset.