The authors aimed to test whether the three classical hypotheses of the interaction between post-traumatic symptomatology and substance use (high risk of trauma exposure, susceptibility for post-traumatic symptomatology, and self-medication of symptoms), may be useful in the understanding of substance use among burn patients. Substance use data (nicotine, alcohol, cannabis, amphetamines, cocaine, opiates, and tranquilizers) and psychopathology measures among burn patients admitted to a burn unit and enrolled in a longitudinal observational study were analyzed. Lifetime substance use information (n = 246) was incorporated to analyses aiming to test the high risk hypothesis. Only patients assessed for psychopathology in a 6-month follow-up (n = 183) were included in prospective analyses testing the susceptibility and self-medication hypotheses. Regarding the high risk hypothesis, results show a higher proportion of heroin and tranquilizer users compared to the general population. Furthermore, in line with the susceptibility hypothesis, higher levels of symptomatology were found in lifetime alcohol, tobacco, and drug users during recovery. The self-medication hypothesis could be tested partially due to the hospital stay cleaning effect, but severity of symptoms was linked to the amount of caffeine, nicotine, alcohol, and cannabis use after discharge. It was found that the 3 classical hypotheses could be used to understand the link between traumatic experiences and substance use explaining different patterns of burn patient's risk for trauma exposure and emergence of symptomatology.