Although stressors appear to motivate marijuana use, and marijuana use, in turn, is believed to induce stress system neuroadaptations, relatively little empirical work has explicitly tested for stress neuroadaptations associated with heavy marijuana use. We examined stressor reactivity to threat of unpredictable electric shock via startle potentiation among heavy marijuana users and a control group that reported minimal history of marijuana use. Heavy marijuana users were randomly assigned to 3 days of marijuana deprivation or no deprivation. This design allowed us to test contrasts for heavy (vs. minimal) use and deprivation (vs. no deprivation) on stressor reactivity. Heavy marijuana users (both deprived and nondeprived) displayed increased startle potentiation during threat of unpredictable electric shock relative to minimal use controls. In contrast, marijuana deprivation had no effect on startle potentiation. Startle potentiation was also increased among users who reported greater stress-coping motives for their marijuana use and users with cannabis use disorder diagnoses. To our knowledge, this is the 1st study to demonstrate increased reactivity to unpredictable stressors among heavy marijuana users. However, comparable increased unpredictable stressor reactivity among patients with alcohol and other substance use disorders has been previously documented. This relationship to heavy marijuana use is consistent with predictions from rodent addiction models regarding stress neuroadaptations following heavy, chronic drug use but could also represent an etiologically relevant premorbid risk characteristic. Finally, the clinical import of unpredictable stressor reactivity is reinforced by its relationships with stress-coping motives and cannabis use disorder status.