Background: Renal cell carcinoma (RCC) accounts for 2% to 3% of all cancers and is the third most common malignancy of the genitourinary tract. Aim: To assess the efficacy and safety of ultrasound guided Rhomboid Intercostal Subserratus Plane Block (RISS) in open nephrectomy surgeries. Patients and methods: This single blinded randomized controlled trial was conducted on 50 patients age (18-65) Years and physical status ASA II, III, scheduled for open nephrectomy. They were randomly assigned into 2 equal groups (25 patients each). Group 1: Thoracic Epidural Block (TEB) group, Group 2: RISS group, the study was done at National Cancer Institute Cairo University from December 2022 to march 2024. Results: Time of 1st rescue analgesia was significantly prolonged in RISS group (5.5 ± 2.29 hrs.) compared to TEB group (3.2 ± 3.08 hrs.) (P value<0.001), however, TEB group (165.9 ± 33.44 mic) was associated with statistically insignificant reduction of intraoperative fentanyl consumption than RISS groups (182.1 ± 43.24 mic) (p value 0.165), As for the NRS score at rest was insignificantly different among the two groups, except at PACU and after 2 hrs,8 hrs. and 10 hrs. was significantly lower in RISS group than TEB group (P value<0.001) and NRS with cough was insignificantly different among the two groups. Conclusion: RISS are effective and safe to perform in open nephrectomy surgery. As it increases the time of 1st rescue of analgesia, provide lower pain score with superiority to ESB compared to TEB.