Central nervous system infections in injection drug users are often devastating in terms of excess morbidity and mortality. In injection drug users with infective endocarditis, embolization from infected valvular vegetations may cause cerebral infarction, intracranial hemorrhage, and the formation of brain abscess. Focal intracranial infections (i.e., brain abscess and spinal epidural abscess) may occur in the absence of infective endocarditis, resulting from bacteremia that seeds the brain or epidural space. Antimicrobial therapy, combined with surgical intervention, may be essential to improve outcome from these neurologic complications. Toxin-mediated diseases (especially tetanus and wound botulism) are also seen in injection drug users. Inoculation of Clostridium spp at injection sites may lead to toxin generation and disease. Clinicians must maintain a high level of suspicion for these diagnoses in injection drug users.