Electronic cigarette (e-cigarette) use has risen dramatically in the United States. Clinically significant fatigue may represent one previously unexplored individual difference factor related to e-cigarette use patterns and e-cigarette specific cognitive processes. Fatigue reflects the experience of being tired, lacking energy, and feeling exhausted. Although fatigue is a normal bodily response, severe or chronic fatigue is maladaptive. Thus, the current study sought to evaluate clinically significant fatigue and its relation to perceived barriers for quitting e-cigarettes, perceived risks and perceived benefits of e-cigarette use, and e-cigarette dependence among 625 adult e-cigarette smokers (51.8% female, Mage = 34.91 years, SD = 10.29). Results indicated that severe fatigue was significantly related to greater perceived barriers to quitting (p < .001), perceived risks (p < .001) and perceived benefits (p < .001) of e-cigarette use, and greater e-cigarette dependence (p < .001); effects that were evident after adjusting for a range of other factors (e.g., combustible cigarette use, pain severity). These novel empirical results highlight the severity of fatigue as a potentially important construct in efforts to better understand beliefs related to e-cigarette use and e-cigarette dependence. Published by Elsevier Ltd.