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Background: Nivolumab or pembrolizumab is the standard second-line treatment for patients (pts) with advanced NSCLC. Anlotinib is an oral VEGFR, FGFR, PDGFR and c-Kit tyrosine kinase inhibitor. The interaction between tumor immune microenvironment and angiogenesis has been well established.This study was designed to assess the benefit and optimal time of nivolumab or pembrolizumab plus anlotinib in previously treated advanced NSCLC. Methods: This is a prospective observational study. Pts with advanced NSCLC who had previous progression after platinum-based chemotherapy were eligible. For NSCLC with EGFR variations pts who had disease progression with prior EGFR TKI therapies and chemotherapy were also eligible. Nivolumab on day 1 (3 mg/kg) every 2 weeks or pembrolizumab on day 1 (200 mg) every 3 weeks for up to 8 weeks, for pts who have no symptomatic deterioration and can benefit from the treatment, then followed by the former therapy plus anlotinib maintenance until progression or unacceptable toxic effects. Anlotinib was given orally 12mg for 2 weeks of a 21-day cycle (days 1-14). The primary outcome was ORR. The secondary outcomes were DCR, PFS, OS and safety. Results: From Mar-2019 to Apr-2021, a total of 19 pts were enrolled. Most were male (84.2%), adenocarcinoma histology (68.4%) and most were treated as second-line treatment (57.9%). 4 had baseline brain metastases. For 8 weeks’ treatment of nivolumab or pembrolizumab monotherapy, 5 pts achieved PR, 8 pts achieved SD and 6 pts had PD; ORR was 26.3%, DCR was 73.7%. During the anti-PD-1 therapy plus anlotinib, 1 pt achieved CR, 12 pts achieved PR (4 of them were PD during monotherapy), 4 pts achieved SD. ORR was 68.4%, DCR was 89.5%. Median PFS was 13.1 months (95% CI 8.6 to14.9). Grade 3 TRAE occurred in 26% pts. 2 pts with squamous cell carcinoma died due to pulmonary embolism and respiratory tract hemorrhage. The most common TRAE were fatigue, hypothyroidism and rash. Conclusions: Anti-PD-1 therapy plus anlotinib has shown promising anti-tumor efficacy compared to the previous anti-PD-1 monotherapy studies for pts with previously treated advanced NSCLC, and with a tolerable safety profile. We may focus on exploring the optimal time and advantage group of this combination in future studies.