Few studies have attempted to characterize how co-occurring risk factors for substance use disorders intersect. A recent study examined this question regarding cigarette smoking and demonstrated that co-occurring risk factors generally act independently. The present study examines whether that same pattern of independent intersection of risk factors extends to illicit drug abuse/dependence using a U.S. nationally representative sample (National Survey on Drug Use and Health, 2011–2013). Logistic regression and classification and regression tree (CART) modeling were used to examine risk of past-year drug abuse/dependence associated with a well-established set of risk factors for substance use (age, gender, race/ethnicity, education, poverty, smoking status, alcohol abuse/dependence, mental illness). Each of these risk factors was associated with significant increases in the odds of drug abuse/dependence in univariate logistic regressions. Each remained significant in a multivariate model examining all eight risk factors simultaneously. CART modeling of these 8 risk factors identified subpopulation risk profiles wherein drug abuse/dependence prevalence varied from <1% to >80% corresponding to differing combinations of risk factors present. Alcohol abuse/dependence and cigarette smoking had the strongest associations with drug abuse/dependence risk. These results demonstrate that co-occurring risk factors for illicit drug/abuse dependence generally intersect in the same independent manner as risk factors for cigarette smoking, underscoring further fundamental commonalities across these different types of substance use disorders. These results also underscore the fundamental importance of differences in the presence of co-occurring risk factors when considering the often strikingly different prevalence rates of illicit drug abuse/dependence in U.S. population subgroups.