Immuno-combination therapy is emerging as an effective treatment for advanced non-small cell lung carcinoma (NSCLC). However, compared to monotherapy, such as monoclonal antibodies or kinase inhibitors, whether combination therapy can enhance antitumor efficacy or alleviate side effects remains unclear.A systematic literature search was undertaken using the PubMed, Embase, Web of Science and Cochrane Central Register of Controlled Trials databases to identify eligible studies concentrating on treatment with erlotinib or erlotinib plus monoclonal antibodies in NSCLC patients published between January 2017 and June 2022. The primary outcomes included progression-free survival (PFS), overall survival (OS), response rate (RR) and treatment-related adverse events (AEs).Seven independent randomized, controlled clinical trials including 1513 patients were obtained for the final analysis. Erlotinib plus monoclonal antibodies was significantly associated with the improvement of PFS (hazards ratio [HR], 0.60; 95% CI 0.53-0.69; z = 7.59, P < 0.01) and with moderate performance regarding OS (HR, 0.81; 95% CI 0.58-1.13; z = 1.23, P = 0.22) and RR (odds ratio [OR], 1.25; 95% CI 0.98-1.59; z = 1.80, P = 0.07), irrespective of EGFR mutation status. In the safety evaluation, erlotinib plus monoclonal antibodies had a markedly higher occurrence of adverse events (AEs) of Clavien grade 3 or higher (OR, 3.32; 95% CI 2.66-4.15; z = 10.64, P < 0.01).Compared with erlotinib alone, combination therapy (erlotinib plus monoclonal antibodies) was associated with significantly improved PFS in NSCLC therapy, accompanied by increased treatment-related AEs.Our systematic review protocol was registered in the PROSPERO international register of systematic reviews (CRD42022347667).Copyright © 2023 Elsevier B.V. All rights reserved.