<h3>Purpose/Objective(s)</h3> Biology-guided Radiotherapy (BgRT) is a new external beam radiotherapy delivery modality combining positron emission tomography-computed tomography (PET-CT) with a linear accelerator. Our research group has previously introduced the BgRT specific prospective process map for developing an initial clinical workflow and has performed the risk analysis for the BgRT process that will bring in a new treatment paradigm. However, due to a lack of experience and historical data, assigning an accurate value of each risk factor in traditional FMEA leads to difficulties for evaluators. Also, there are certain sub-processes where the differences in weights of risk factors needs to be considered. Therefore, in this study, we introduced the fuzzy FMEA to perform a comprehensive analysis of failure modes (FMs) of BgRT and overcome weaknesses of conventional FMEA. <h3>Materials/Methods</h3> Five sub-processes unique to BgRT out of a total of 15 sub-processes were selected and relevant 84 FMs were identified. The evaluators used the fuzzy linguistic variables (very low, low, medium, high, and very high) to evaluate the importance of risk factors for assigning weights as well as the evaluation of each risk factor (occurrence, severity, and detectability) of each failure mode. Then, the fuzzy measure was used to calculate the weights of risk factors and the fuzzy integral method was used to fuse every value of risk factor of FMs to obtain the final fuzzy risk priority number value. <h3>Results</h3> Top 3 FMs are the machine down/emergency during beam delivery, failure to meet activity before PET pre-scan, and failure/delay of tracer delivery from a local vendor. The mitigation plans are discussed by team members including complete guidelines for the emergencies on the treatment machine, maintenance program of PET tracers by dedicated staffs, and staff training program for the BgRT procedure. Strong cooperation with a local PET tracer vendor and timely patient scheduling to allow multiple PET images at the treatment machine were also included in mitigation plans. <h3>Conclusion</h3> The proposed fuzzy FMEA presents a more reasonable and effective method for assessing potential failures allowing fuzzy linguistic variables terms that are easier to use than numerical assignments to evaluate the FMs, especially with the new prototype machine for BgRT. The results have been shared with team members, and mitigation plans will be implemented.