Background: Cancer pain is one of the most frequent and relevant symptoms in cancer patients and impacts on patient’s quality of life. International and local standards recommend as an initial strategy the use of an analgesic scheme composed of strong opioids associated with adjuvants such as acetaminophen, based upon the assumption that combining drugs could have a better analgesic effect, could allow lowering opioid dosing, and could prevent the occurrence of adverse effects of opioids. However, there is uncertainty about the impact of acetaminophen as an adjuvant in patients who use strong opioids for moderate to severe pain management in cancer patients. The aim of this study is to assess the efficacy and safety of intravenous acetaminophen associated with strong opioids in hospitalized adult cancer patients who have moderate to severe cancer-related pain. Methods: We will perform a randomized double-blinded controlled study comparing intravenous acetaminophen 1 g 4 times a day versus placebo for 48 h as an adjuvant to strong opioids. We will assess pain intensity as a primary outcome, using the verbal numerical rating scale (VNRS, I0 to 10 scale with higher scores meaning higher pain intensity), and we will compare the mean difference in pain intensity between baseline and 48 h among the placebo and intervention groups. We estimate that a decrease of 1 point in the VNRS would be clinically significant. Assuming a standard deviation in pain intensity of 1.7 points, an alpha of 0.025, and a power of 0.8, we estimate a sample size of 112 patients, with 56 patients in each arm. Secondary outcomes include the difference in total opioid use between baseline and at 48 h among the groups, and adverse effects such as drowsiness, constipation, nausea, and vomiting would be evaluated. Discussion: The randomized, double-blind, placebo-controlled design is the best strategy to assess the efficacy of acetaminophen as an adjuvant in adult cancer patients with moderate to severe pain who are receiving strong opioids. We expect to contribute to national and international guidelines with these results. Trial registration: Clinicaltrials.gov NCT04779567. Registered on March 3, 2021. Retrospectively registered.