Abstract Introduction Tyrosine kinase (TKI) and checkpoint inhibitors (CI) prolonged overall survival in metastatic renal cell carcinoma (mRCC). Early prediction of treatment response is highly desirable for the individualization of patient management and improvement of therapeutic outcome; however, serum biochemistry is unable to predict therapeutic efficacy. Therefore, we compared ¹⁸F-PSMA-1007 PET imaging for response assessment in mRCC patients undergoing TKI or CI therapy compared to CT-based response assessment as the current imaging reference standard. Methods ¹⁸F-PSMA-1007 PET/CT was performed in mRCC patients prior to initiation of systemic treatment and 8 weeks after therapy initiation. Treatment response was evaluated separately on ¹⁸F-PSMA-PET and CT. Changes on PSMA-PET (SUV_mean) were assessed on a per patient basis using a modified PERCIST scoring system. Complete response (CR_PET) was defined as absence of any uptake in all target lesions on posttreatment PET. Partial response (PR_PET) was defined as decrease in summed SUV_mean of > 30%. The appearance of new, PET-positive lesions or an increase in summed SUV_mean of > 30% was defined as progressive disease (PD_PET). A change in summed SUV_mean of ± 30% defined stable disease (SD_PET). RECIST 1.1 criteria were used for response assessment on CT. Results of radiographic response assessment on PSMA-PET and CT were compared. Results Overall, 11 mRCC patients undergoing systemic treatment were included. At baseline PSMA-PET₁, all mRCC patients showed at least one PSMA-avid lesion. On follow-up PET₂, 3 patients showed CR_PET, 3 PR_PET, 4 SD_PET, and 1 PD_PET. According to RECIST 1.1, 1 patient showed PR_CT, 9 SD_CT, and 1 PD_CT. Overall, concordant classifications were found in only 2 cases (2 SD_{CT + PET}). Patients with CR_PET on PET were classified as 3 SD_CT on CT using RECIST 1.1. By contrast, the patient classified as PR_CT on CT showed PSMA uptake without major changes during therapy (SD_PET). However, among 9 patients with SD_CT on CT, 3 were classified as CR_PET, 3 as PR_PET, 1 as PD_PET, and only 2 as SD_PET on PSMA-PET. Conclusion On PSMA-PET, heterogeneous courses were observed during systemic treatment in mRCC patients with highly diverging results compared to RECIST 1.1. In the light of missing biomarkers for early response assessment, PSMA-PET might allow more precise response assessment to systemic treatment, especially in patients classified as SD on CT.