Background The underexplored potential of PD-L1 blockade in advanced renal cell carcinoma highlights an urgent need for novel agents. This trial aimed to compare benmelstobart (a novel PD-L1 inhibitor) plus anlotinib with sunitinib as first-line treatment for advanced renal cell carcinoma. Methods ETER100 was a multicentre, randomised, open-label, phase 3 trial conducted at 37 medical sites in China. We included patients aged 18-80 years, who had previously untreated, advanced, clear-cell renal cell carcinoma, and an Eastern Cooperative Oncology Group performance status of 0 or 1. We randomly assigned (1:1) patients to receive either benmelstobart (intravenous, 1200 mg, once every 3 weeks) plus anlotinib (oral, 12 mg, once daily for the first 2 weeks of a 3-week cycle) or sunitinib (oral, 50 mg, once daily for the first 4 weeks of a 6-week cycle) until disease progression, unacceptable toxicity, investigator's decision, or patient withdrawal. Randomisation was done centrally with stratified block randomisation (block size 4) and stratified by International Metastatic Renal Cell Carcinoma Database Consortium risk. The primary endpoint was progression-free survival as assessed by blinded independent central review according to the Response Evaluation Criteria in Solid Tumours version 1.1 in the full analysis set (ie, randomly assigned patients who received at least one dose of study drug without the violation of key inclusion criteria) and per-protocol set (ie, randomly assigned patients who received at least one cycle of protocol treatment without major protocol violations and had at least one efficacy assessment). In this Article, we report the results of a prespecified interim analysis. This ongoing study, closed to recruitment, is registered with ClinicalTrials.gov, NCT04523272. Findings Between Aug 25, 2020, and Feb 6, 2023, we assessed 687 patients for eligibility, 531 (77%) of whom were randomly assigned to receive either benmelstobart plus anlotinib (266 [50%] patients) or sunitinib (265 [50%] patients). 527 (99%) patients were included in the full analysis set (263 [50%] patients who received benmelstobart plus anlotinib and 264 [50%] who received sunitinib). All patients were Chinese (400 [76%] men and 127 [24%] women), with a median age of 60 years (IQR 54-67). As of the cutoff date (Jan 31, 2024), the median followup was 22<middle dot>8 months (IQR 15<middle dot>2-29<middle dot>7). In the full analysis set, median progression-free survival was significantly longer with benmelstobart plus anlotinib than with sunitinib (19<middle dot>0 months [95% CI 15<middle dot>3-22<middle dot>8] vs 9<middle dot>8 months [8<middle dot>4-12<middle dot>4]; hazard ratio [HR] 0<middle dot>53 [95% CI 0<middle dot>42-0<middle dot>67]; p<0<middle dot>0001). In the per-protocol set, median progression-free survival was 19<middle dot>0 months (16<middle dot>5-22<middle dot>8) in the benmelstobart-anlotinib group versus 11<middle dot>0 months (8<middle dot>5-13<middle dot>6) in the sunitinib group (HR 0<middle dot>55 [0<middle dot>43-0<middle dot>70]; p<0<middle dot>0001). The most common grade 3 or worse treatment-related adverse event was hypertension (occurring in 91 [34%] of 264 patients in the benmelstobart-anlotinib group vs 55 [21%] of 264 in the sunitinib group). Serious treatment-related adverse events occurred in 63 (24%) patients in the benmelstobart-anlotinib group and in 42 (16%) patients in the sunitinib group. In the benmelstobart-anlotinib group, three (1%) deaths occurred due to treatment-related adverse events (one each with cardiac-respiratory arrest, unknown reason, and renal failure) and no deaths occurred in the sunitinib group. Interpretation Benmelstobart plus anlotinib improved progression-free survival compared with sunitinib among patients with previously untreated, advanced clear-cell renal cell carcinoma. These findings suggest the potential of benmelstobart plus anlotinib as a treatment option for this population.