A 48-year-old man participating in a residential treatment program was treated with gatifloxacin for a urinary tract infection. While taking the antibiotic, two urine screens were positive for opiates; results of previous urine opiate screens had been negative. Confirmatory tests using a different assay method, however, gave negative results for opiates. Two weeks after completing gatifloxacin therapy, the patient's urine screen was negative for opiates. Application of the Naranjo adverse drug reaction probability scale indicated that gatifloxacin probably was associated with this patient's positive urine opiate screen. Fluoroquinolones as a class are among several compounds that have demonstrated a propensity to cross-react with enzyme immunoassay urine drug screens for opiates. Occurrence of cross-reactivity appears to vary among individual assays. The mechanism by which fluoroquinolones cross-react with the immunoassay is unknown. Falsepositive results could have negative effects on patient care, and ramifications of a positive drug screen include possible dismissal from a substance abuse treatment program. Confirmatory analysis using a different assay method is therefore necessary to verify the presence of the target drug.