Patients with central nervous system (CNS) infections are increasingly treated with intravenous antimicrobials outside the hospital, but the safety and problems associated with this therapy have not been well defined. To examine this issue, we reviewed 68 cases in which outpatient intravenous antimicrobial therapy (OPAT) was received through our physician office-based infusion clinic. All infections were cured, and no deaths occurred during therapy. Seizures occurred in 2 patients but without significant injury and apparently were unrelated to antimicrobial therapy. Eleven patients (16%) were hospitalized after starting OPAT, 5 for procedures and 6 for medical reasons. The antimicrobial used was changed in 13 cases (19%) because of an adverse effect or clinical failure. OPAT can be safe and effective for patients with CNS infections, but patients must be carefully selected and monitored closely.