Purpose <p>This prospective study examined whether ¹⁸F-AlF-NOTA-fibroblast activation protein inhibitor (FAPI)-04 (denoted as ¹⁸F-FAPI-04) positron emission tomography/computed tomography (PET/CT) can detect the development and severity of radiation esophagitis (RE) in patients with locally advanced esophageal squamous cell carcinoma (LA-ESCC) treated with concurrent chemoradiotherapy.</p> Materials and methods <p>From June 2021 to March 2022, images were collected from LA-ESCC patients who underwent ¹⁸F-FAPI-04 PET/CT examinations before and during radiotherapy. The development of RE was evaluated weekly according to Radiation Therapy Oncology Group criterion. The target-to-background ratio in blood (TBR_blood) was analyzed at each time point and correlated with the onset and severity of RE. Factors that predicted RE were identified by multivariate logistic analyses.</p> Results <p>Thirty patients were evaluated. Significantly higher TBR_blood (during radiotherapy, <i>P</i> = 0.003) and change in TBR_blood compared with pre-RT (ΔTBR_blood, <i>P</i> = 0.002) were observed in patients with RE than patients without RE. Those with grade 3 RE had a significantly higher TBR_blood (during radiotherapy, <i>P</i> = 0.003) and ΔTBR_blood (<i>P</i> = 0.003) compared with those with RE &lt; grade 3. On multivariate analysis, ΔTBR_blood was identified as a significant detection of any grade RE (<i>P</i> = 0.021) and grade 3 RE (<i>P</i> = 0.038).</p> Conclusion <p>The ΔTBR_blood on ¹⁸F-FAPI-04 PET/CT may be effective at identifying patients with RE, especially grade 3 RE.</p>