Background: Cabozantinib (Cabo) is approved for mRCC patients based on the METEOR and CABOSUN trials. The real-world effectiveness of Cabo in mRCC patients in the first- (1L), second- (2L), third- (3L) and fourth-line (4L) settings requires characterization. Methods: This retrospective analysis included mRCC patients who were treated with Cabo and stratified using IMDC risk groups. Overall response rate (ORR), time to treatment failure (TTF), and overall survival (OS) were calculated. Results: A total of 413 patients (82.6% with clear cell and 17.4% non-clear cell) were identified. The median age was 57 years. Overall, 63% of patients had a Karnofsky performance status score of >80 and 82.6% had prior nephrectomy. 23.1%, 75.4% and 88.3% of patients received immunotherapy as a prior line of treatment, before receiving Cabo in the 2L, 3L and 4L settings, respectively. For patients treated with 1L PD(L)1 combination or monotherapy (n=31), 2nd line Cabo had ORR of 20.8%, median TTF of 5.4 months and median OS of 17.4 months. When segregated into IMDC favorable, intermediate, and poor risk groups, the median OS was 34.8 months (95% CI 5.52-NR), 18.0 months (12.3-35.6) and 9.8 months (7.4-20.8), p=0.0088, respectively for 2L Cabo; and 31.5 months (23.6-39.3), 20.5 months (10.1-21.8), and 6.9 months (4.1-10.9), p=<0.0001), respectively for 3L Cabo. Conclusions: The ORR and TTF of Cabo were maintained from the 1L to the 4L therapy settings. In the 2L and 3L settings, the IMDC criteria appropriately stratified patients into favorable, intermediate and poor risk groups for OS. Cabo has activity after first line immunotherapy.