Background <p>The analgesic effect of transdermal fentanyl (TDF) differs among cancer pain patients. This study aims to investigate the relationship between clinical factors and pain relief when using TDF in cancer pain patients who rotate from oral opioids to TDF.</p> Methods <p>A two-center retrospective study was conducted in Chongqing University Cancer Hospital and Sichuan Cancer Hospital, including adult cancer pain patients who rotated from oral opioids to TDF between 2018 and 2022. Based on the clinical characteristics, logistic regressions and directed acyclic graphs (DAG) were employed to identify significant factors influencing the efficacy of TDF. The study adhered to STROBE guidelines.</p> Results <p>This survey included 359 patients, among them, 254 patients (70.8%) attained good pain relief after rotating to TDF. 59.3% of patients utilized TDF at standard dosage, while 24.8% used underdose TDF, with only 52.8% achieving adequate pain relief, significantly lower than other groups (<i>p</i> &lt; 0.001). Initial univariable analysis of 22 clinical factors among the standard dose group showed that a higher body mass index (BMI, median 23.2&#xa0;kg/m² vs. 21.0&#xa0;kg/m², OR = 0.83 [0.75–0.91], <i>p</i> &lt; 0.001) and the presence of lung cancer (OR = 0.31 [0.11–0.89], <i>p</i> = 0.030) predicted potentially unsatisfactory pain control after TDF treatment. Subsequently, a multivariable regression analysis based on DAG-directed factor selection identified BMI (OR = 0.82 [0.74–0.92], adjusted <i>p</i> &lt; 0.01) as the only independent factor influencing TDF effectiveness.</p> Conclusions <p>Our study suggested that high BMI was a significant predictor of poor cancer pain relief when rotating from oral opioids to TDF, and provides a useful measurement of managing adult cancer pain when using TDF.</p> Trial registration <p>ClinicalTrials.gov, NCT06369961, registered on April 11, 2024; <a href="https://clinicaltrials.gov/study/NCT06369961">https://clinicaltrials.gov/study/NCT06369961</a>.</p>