Cotton fever is a benign, self-limited syndrome that may mimic sepsis in intravenous drug addicts. We present an illustrative case and a review of the literature. Serious illness such as pneumonia and infectious endocarditis must always be considered in febrile addicts. However, trivial illness accounts for 16% to 26% of such fevers. Recent evidence suggests that emergency physicians are able to diagnose trivial illness with 93% specificity in febrile adult drug addicts. Short-term observation units may be an alternative to hospital admission for febrile drug users with a presumptive diagnosis of trivial illness and in those in whom the diagnosis of cotton fever is entertained.