Background: PD-L1 has emerged as a potential biomarker for predicting responses to immunotherapy and as a prognostic factor in non-small cell lung cancer (NSCLC). In this network meta-analysis, we aimed to evaluate the efficacy of first-line PD-(L)1 monotherapy in advanced NSCLC patients with high PD-L1 expression. Methods: We conducted a systematic search in PubMed to identify all eligible trials from inception until 1 November 2020, with no start date limit applied. Only phase III trials evaluating the efficacy of first-line (1L) PD-(L)1 monotherapy in patients with stage IIIB/stage IV NSCLC and high PD-L1 expression were included. Results: Six clinical trials (KEYNOTE-024, KEYNOTE-042, EMPOWER Lung-01, IMpower110, MYSTIC and CheckMate-026) with 2,111 patients were included. In head-to-head comparisons, immunotherapy showed a significant improvement in progression-free survival (PFS: HR_pooled = 0.69, 95% CI: 0.52-0.90, p = 0.007), overall survival (OS: HR_pooled = 0.69, 95% CI: 0.61-0.78; p< 0.001) and overall response rate (ORR) (Risk ratio [RR]_pooled = 1.354, 95% CI: 1.04-1.762, p = 0.024) compared to chemotherapy (CT). In the assessment of relative efficacy for PFS through indirect comparisons, pembrolizumab (results from KEYNOTE-024) ranked highest followed by cemiplimab and atezolizumab, with statistical significance determined across some of the drugs. In terms of OS, cemiplimab ranked highest followed by atezolizumab and pembrolizumab, although non-significant OS was determined across these drugs. Overall, 1L PD-(L)1 monotherapy improved OS in almost all subgroups, reaching statistical significance in men (HR_pooled = 0.624, 95% CI: 0.51-0.72, p< 0.001), non-Asian patients (HR_pooled = 0.66, 95% CI: 0.55-0.79, p< 0.001), all patients regardless of age ( < 65 years [HR_pooled = 0.72, 95% CI: 0.57-0.90, p = 0.005]; ≥65 years [HR_pooled = 0.61, 95% CI: 0.48-0.77, p< 0.001]), ECOG PS status (ECOG PS = 0 [HR_pooled = 0.68, 95% CI: 0.56-0.82, p< 0.001; ECOG PS = 1 [HR_pooled = 0.59, 95% CI: 0.43-0.82, p = 0.001) and histological tumour type (Squamous [HR_pooled = 0.49, 95% CI: 0.37-0.67, p< 0.001; Non-squamous [HR_pooled = 0.67, 95% CI: 0.52-0.87, p = 0.003). In the case of smokers and NSCLC stage, only current/former smokers (HR_pooled = 0.623, 95% CI: 0.47-0.83, p = 0.001) and patients with stage IV disease* (HR_pooled = 0.687, 95% CI: 0.59-0.81, p< 0.001) benefited from single PD-(L)1 monotherapy over CT. Conclusions: PD-(L)1 inhibitor monotherapy improves efficacy outcomes in the 1L setting of advanced NSCLC patients with high PD-L1 expression. Current/former smokers ≥65 years, with ECOG PS = 1 and squamous NSCLC benefited most from this therapy. *KEYNOTE-042 was the only study including patients with stage IIIB NSCLC.