Background: Immunotherapy has unequal efficacies in populations with different clinical or histological features. This study aims to explore inter-subgroup differences in responses to immunotherapy in patients with advanced non-small cell lung cancer (NSCLC) and find the optimal treatments for each subgroup. Methods: We performed (network) meta-analyses of phase III random controlled trials, in which efficacies of 10 immunotherapy-based treatments were compared, including anti-programmed death receptor-1 (PD-1) (+chemotherapy), anti-programmed death ligand-1 (PD-L1) (+chemotherapy), anti-PD-L1+anti-cytotoxic T-lymphocyte protein 4 (CTLA-4), anti-PD-1+anti-CTLA-4 (+chemotherapy), anti-CTLA-4+chemotherapy, anti-PD-1+anti-angiogenic therapy (AT)+chemotherapy, and anti-PD-L1+AT+chemotherapy, for 19 subgroups by sex, age, smoking status, metastatic site (liver/brain/bone), histological type (squamous/non-squamous cancer), and PD-L1 expression, using hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS) and their 95% confidence intervals (CIs). Results: 22 studies comprised of 12678 patients with advanced NSCLC were included in our study. The results showed OS and PFS advantages of immunotherapy-based treatments in 16 out of 19 subgroups comparing with chemotherapy. Never-smokers (OS-HR 0.81, 95% CI 0.55-1.18; PFS-HR 0.73, 95% CI 0.51-1.07), ¡Ý75-year-old patients (OS-HR 0.9, 95% CI 0.71-1.13), and patients with liver metastases (OS-HR 0.88, 95% CI 0.77-1) showed indisposed responses to immunotherapy. In patients with PD-L1 tumor proportion score (TPS)<1%, anti-CTLA-4+anti-PD-1 and anti-PD-1+anti-CTLA-4+chemotherapy had significant OS benefit comparing with anti-PD-L1 monotherapy (HR 0.6, 95% CI 0.44-0.81; HR 0.6, 95% CI 0.41-0.87; respectively) and anti-PD-L1+AT+chemotherapy (HR 0.66, 95% CI 0.48-0.92; HR 0.66, 95% CI 0.45-0.98; respectively). In patients with liver metastases, anti-PD-L1+AT+chemotherapy showed significant PFS advantage comparing with anti-PD-L1+chemotherapy (HR 0.51, 95% CI 0.33-0.77). As for other populations, anti-PD-1+chemotherapy showed wide-ranging promising efficacies in multiple subgroups. Conclusions: Patients with advanced NSCLC generally benefit from immunotherapy. Specific immunotherapy treatments should be applied according to different clinical or histological features. Meanwhile, we expect more preclinical and clinical studies to focus on therapeutic strategies for populations with impaired responses towards immunotherapy. Funding: CSCO-BMS Oncologic Research Foundation (Grant No. Y-BMS2019-100); Guangdong Provincial Key Lab of Translational Medicine in Lung Cancer (Grant No. 2017B030314120) and Guangdong Association of Clinical Trials (GACT); Changsha Science and Technology Bureau (Grant No. kq1907077).