Pain is the most common reason people see doctors in developed Countries and a very common cause of access in Emergency Department (ED). The combination acetaminophen/codeine represents the standard medication in the second step of the WHO analgesic scale and codeine is one of the most commonly used opioid analgesic for a variety of pain conditions. However, many aspects related to safety and efficacy are still undefined. To summarize and review the results of the most relevant studies on the efficacy and safety profile of acetaminophen/codeine combination in the treatment of pain of different origin. We performed a literature search to identify and evaluate all relevant english-language randomized controlled trials (RCTs), meta-analyses and reviews about the codeine plus paracetamol combination in the treatment of pain from any source. Acetaminophen/codeine combination is effective in the treatment of moderate to severe pain in all setting analyzed in this study, which include headache, postoperative, osteoarticular and post-traumatic. The best results in terms of safety and efficacy have been obtained in postoperative pain. Efficacy of acetaminophen/codeine combination is not inferior to NSAIDs. Acetaminophen/codeine combination is effective in the treatment of pain, through a synergistic action of the two molecules, and is not inferior to NSAIDs. Side effects of acetaminophen/codeine are usually minor, differently from NSAIDs, which may induce some potentially life threatening conditions.