OBJECTIVES: CRO is efficacious for persistent moderate to severe osteoarthritis pain based on well-controlled trials. Additionally, decision-makers require evidence of effectiveness in routine practice, and cost-effectiveness compared to standard therapy. METHODS: Open-label, active-controlled, randomized, naturalistic four-month study of analgesic effectiveness and cost-effectiveness of CRO vs. oxy/APAP. Outcomes and resource use were collected by telephone. Effectiveness was measured in 485 patients as the proportion having at least 20% improvement from baseline in Western Ontario and McMaster Universities Osteoarthritis Index pain score. Quality-adjusted-life-years (QALYs) were calculated from Health Utilities Index-3 scores. Cost-effectiveness was measured as cost/patient improved and QALYs gained from societal and health care perspectives using generic oxy/APAP (base case). Uncertainty was evaluated using multiple one-way sensitivity analyses and cost-effectiveness acceptability curves. RESULTS: In total, 62.2% vs. 45.9% (p=0.0003) of patients improved with CRO and oxy/APAP respectively. Mean QALYs gained over four months with CRO compared to oxy/APAP was 0.0105 (p=0.1673). Mean societal cost/patient over four months was US$6792 vs. US$6929 (p=0.3345) for CRO and oxy/APAP, respectively. CRO was both more effective and less costly than oxy/APAP using the societal perspective (includes costs associated with time loss). Using a health care perspective (excludes costs associated with time loss), cost-effectiveness of CRO was US$4,500/patient improved and US$69,856/QALY gained. CONCLUSIONS: From the societal perspective, CRO was both more effective and less costly than oxy/APAP. From the health care perspective, CRO compared to generic oxy/APAP fell within the acceptable range of cost-effectiveness if decision-makers were willing-to-pay between US$50,000/QALY and US$100,000/QALY. These findings should be considered in decisions about treating osteoarthritis pain.