Bupropion is a commonly prescribed, monocyclic antidepressant often used as an aid for smoking cessation. Several case reports have described false positive amphetamine urine drug screens (UDS) associated with bupropion. We sought to determine whether false positive amphetamine UDS due to the use of bupropion would be a frequent occurrence. We conducted an IRB-approved, retrospective chart review of all emergency department patients who underwent UDS between 1 January 2006 and 31 July 2007. All urine samples were screened using Syva EMIT II Plus immunoassay reagents. All positive screens underwent confirmation by gas chromatography (GC). We reviewed the records of patients with positive amphetamine UDS. We documented prescription use of bupropion, other antidepressants, stimulants, antipsychotics, and anti-hypertensives. We recorded evidence of polysubstance abuse (PSA) as patients who had had a documented diagnosis or laboratory evidence of abuse of at least two substances (drugs or ethanol). Of 10,011 urine drug screens, 362 (3.6%) were positive for amphetamine. GC confirmed amphetamines in 234 (65%), but failed to confirm in 128 (35%). Among the 234 confirmed, records reflected use of bupropion in three (1.3%), other antidepressants in 38 (16%), antipsychotics in 17 (8%), and amphetamine in 50 (21%). Records indicated evidence of PSA in 55 (24%). Among the 128 which failed to confirm, records reflected prescription use of bupropion in 53 (41%). None whose drug screen failed to confirm had evidence of PSA. Therapeutic use of bupropion appears to be the most frequent cause of false positive urine drug screens for amphetamines in our population.