High rates of co-occurrence between posttraumatic stress (PTS) and substance use disorders (SUDs) have led to the suggestion that substance use among individuals experiencing PTS symptoms might serve a self-medication function. However, research is still needed to provide a more comprehensive evaluation of the unique associations between PTS symptom clusters and substances (licit and illicit) with both anxiolytic/depressant and stimulant properties. Consequently, this study examined the relationship between severity of different PTS symptom clusters and heroin, crack/cocaine, and alcohol dependence among 48 treatment-seeking SUD patients with a history of traumatic exposure. No evidence was found for a relationship between PTS symptom clusters and crack/cocaine or alcohol dependence; however, results suggested a relationship between hyperarousal and avoidance (inversely related) symptoms and heroin dependence. Results are discussed in terms of their implications for understanding motivations underlying the substance of choice among individuals with PTS symptoms, as well as the development of treatments for co-occurring PTS and SUDs.