Background: Analgesics are an essential component of the treatment of cancer-associated pain. Pharmacologic treatment is usually begun with nonopioid analgesics, most frequently acetaminophen. If pain relief is not achieved, the so-called “weak” opioids, such as codeine and hydrocodone, may be used in combination with acetaminophen. Adverse effects (AEs) of the opioids include constipation, somnolence, nausea, and vomiting. Based on the results of a literature search, data comparing the effects of the opioids are lacking. Objective: The purpose of this study was to compare the analgesic efficacy and tolerability of codeine phosphate versus hydrocodone bitartrate in combination with acetaminophen in the relief of cancer-related pain. Methods: This 23-day, prospective, double-blind, randomized, parallel-group study was conducted at 3 Colombian centers: University Libre, Social Security Institute, and General Hospital of Medellín, Cali, Colombia. Outpatients with cancer were eligible for the study if they were aged >-18 years and had chronic (duration, ≥ 3 months) moderate to severe cancer-related pain (score on 10-cm visual analog scale [VAS], > 3 cm [moderate]; score on a 4-point verbal pain-intensity scale, > 1 [moderate]). Eligible patients were randomly assigned to receive 1 tablet of codeine/acetaminophen (C/A) 30/500 mg or hydrocodone/acetaminophen (H/A) 5/500 mg PO q4h (total daily doses, 150/2500 and 25/2500 mg, respectively) for 23 days. In both groups, if pain intensity was rated as > 3 on the VAS at week 1 or 2, the dosage was doubled. The primary end point was the proportion of patients who achieved pain relief (defined as a score of > 1 on a 5-point verbal rating scale [VRS] (0 = none; 1 = a little; 2 = some; 3 = a lot; and 4 = complete) on study days 1 and 2 and weeks 1, 2, and 3. The secondary end point was the proportion of patients in whom pain was decreased (VAS score, <- 3 cm). AEs were self-reported on a 4-point VRS (0 = absent; 1 = mild; 2 = moderate; and 3 = severe). Results: Of the 121 patients who participated, 59 received C/A and 62 received H/A. Of the total number of cases, 59% were aged 60 to 89 years, and 55% were men. At baseline, 88% of the patients described their pain intensity as moderate; 12%, severe. Of the patients who received C/A, 58% responded to the initial dosage of 150/2500 mg/d, and 8% of the patients responded to the double dosage; 34% did not experience pain relief. In patients with H/A, pain was reported as absent or mild in 56% of patients at the starting dosage of 25/2500 mg/d; an additional 15% of the patients responded to the double dosage; the remaining 29% of patients did not experience any pain relief. None of the between-group differences in response rates were significant. The most common AEs in the C/A and H/A groups were constipation (36% and 29%, respectively), dizziness (24% and 19%), vomiting (24% and 16%), and dry mouth (15% and 18%), with no significant differences between groups. Conclusion: In this study, efficacy and tolerability were comparable between C/A and H/A over 23 days of treatment in these patients with moderate or severe, chronic, cancer-related pain.