Patient-controlled analgesia (PCA) is a widely used delivery system for intravenous (IV) administration of opioids during acute post-operative pain management. Various opioids have been used for IV PCA including morphine, meperidine, hydromorphone, and fentanyl. Morphine is by far the most commonly used opioid in this setting, yet the selection of morphine as the primary opioid is based largely on tradition. Meperidine should not be considered in the PCA armamentarium due to the associated risk of central nervous system toxicity from its metabolite normeperidine. The objective of this study is to compare the rate of opioid-induced adverse reactions among three IV PCA opioids, fentanyl, morphine, and hydromorphone, in acute post-operative pain management. Although morphine is the most frequently used opioid, the results from three US hospitals indicate that fentanyl IV PCA had a significantly lower rate of common opioid induce adverse reactions (nausea/vomiting, pruritus, urinary retention, or sedation), when compared to IV PCA morphine and hydromorphone in acute post-operative pain management. The median pain score on post-operative day-1 and -2 was significantly lower in fentanyl IV PCA group. The quantity of opioid in each group was not significantly different when converted to an analgesic equivalence. Morphine and hydromorphone IV PCA were no different in rates of adverse reactions in any area; although, the hydromorphone group trended toward a lower pruritus and urinary retention rate compared to morphine, but this was not statistically significant. The rate of respiratory depression was not significantly different between the three opioids. Fentanyl IV PCA is an under used opioid for post-operative acute-pain management and should be considered more often due to the lower adverse reaction profile.