BACKGROUND Codeine is a lawfully permitted ingredient of over-the-counter cold and cough medicines readily available to the public in Taiwan. Drug abusers often use it as a substitute for morphine and heroin, attributing the morphine in the urine test to therapeutic cough medicine. In the literature, several criteria for taking codeine, using a single large-dose model, have been proposed. Here, we evaluate whether these criteria still fit in therapeutic situation. METHODS Ten healthy volunteers each received, over two days, a total of 8 doses of cough syrup containing 4.5 mg of codeine phosphate per dose. Urine specimens were collected regularly during and in the 3 days after syrup consumption. The urine specimens were analyzed by an enzyme immunoassay screening test and a gas chromatography-mass spectrometry (GC-MS) confirmation test. RESULTS Positive screen was noted during syrup use and 12-30 hours after the last dose of medication. The morphine:codeine ratio was < 1 during syrup use and 12 hour after the last dose of syrup. In only 1.4% of the urine specimens was the morphine:codeine ratio 1-3.0, and in these, the concentrations of morphine and codeine were both below 300 ng/mL. CONCLUSIONS The results are compatible with the findings of the single large-dose model and may be used as a reference for the interpretation of urine analysis after the intake of multiple therapeutic doses of cough syrup with codeine.