Background: and Objective: With the advancement of cancer treatments and increased life expectancy, managing breakthrough cancer pain (BTcP) is essential to improve the quality of life for cancer patients. This study aimed to compare the major rapid onset opioids in Korea based on their characteristics and costs to determine the best option for each patient. Methods: Based on sales information from IQVIA-MIDAS, sublingual fentanyl tablet (SLF), fentanyl buccal tablet (FBT), and oral transmucosal fentanyl citrate (OTFC) were selected as the top three drugs for the treatment of BTcP in Korea, considering them the most comparable drugs. The cost and cost-pain relief ratio of the drugs for short-term (1 month) and long-term (1 year) treatment were compared and the ease of administration based on various factors, including pharmacokinetics, onset of action, and administration procedures were evaluated. Results: SLF was evaluated as the best overall in terms of rapid onset of action, ease of administration, and drug cost and also had the highest market share. SLF had the lowest cost pain relief ratio for both the initial and supplemental treatment for the 1-month pain intensity difference 15 (PID15) ratio. However, for the 1-month PID30 ratio, SLF was not superior to OTFC or FBT. The longer the breakthrough cancer pain duration, the more cost-effective the other rapid onset opioids. Conclusion The rapid onset opioids that fit the patient’s breakthrough cancer pain pattern have the best cost-effectiveness.