Few qualitative studies have explored the relationship between substance use and self-harm. We employed a multiple-case study research design to analyze data from 80 patients who were admitted to a hospital in South Africa following self-harm. Our analysis revealed, from the perspective of patients, a number of distinct ways in which substance use is implicated in self-harm. Some patients reported that substance intoxication resulted in poor decision making and impulsivity, which led to self-harm. Others said substance use facilitated their self-harm. Some participants detailed how in the past their chronic substance use had served an adaptive function helping them to cope with distress, but more recently, this coping mechanism had failed which precipitated their self-harm. Some participants reported that substance use by someone else triggered their self-harm. Findings suggest that there are multiple pathways and a host of variables which mediate the relationship between substance use and self-harm.