Abstract Immune checkpoint inhibitors (ICIs) have become new research hotspots in the treatment of non-small cell lung cancer, but the efficacy and safety of immunotherapy for patients with chronic viral infection are still unclear, because existing clinical trials often exclude those patients. Materials and Methods We identified 78 locally advanced or advanced NSCLC patients with chronic viral infection treated with PD-1/PD-L1 inhibitors alone or combined with the chemotherapy/bevacizumab therapy, of whom 60 with hepatitis B, 2 with hepatitis C, and 16 with syphilis. Objective response rates were assessed using the RECIST v1.1. Adverse events were graded following the National Cancer Institute Common Terminology Criteria for Adverse Events v5.0. Results Objective responses were observed in 19 out of 78(24.36%) patients, and the disease control rate (DCR) was 69.23% (54/78). No patient achieved a complete response. The median progression-free survival (PFS) was 6.49 months (95% CI:3.71-9.27). PFS was 1.44 months (95%CI:0.00-4.34) for monotherapy versus 7.34 months (95%CI:4.50-10.18) for combination therapy (P=0.053). Patients in the first-line treatment group revealed relatively higher ORR and longer PFS (ORR: 48.00% vs. 13.20%, P = 0.001; PFS: 7.67 months vs. 5.57 months, P = 0.129). Patients with combined radiotherapy showed longer PFS than those without combined radiotherapy (14.07 vs.4.62, P=0.027). The incidence of adverse events of any grade was 73.07% (57/78), among which there were 7 cases of grade 4 adverse events. The incidence of leukopenia in any grade of adverse reactions was the highest (57.69%), followed by anemia (25.64%), elevated alanine aminotransferase or aspartate aminotransferase (24.36%) and fatigue (21.79%). Hepatic transaminase increased in 26.7% (16/60) of HBV-infected patients, and remained unchanged in 63.3% (38/60) patients. Conclusions The PD-1 inhibitor showed an acceptable toxicity profile and moderate efficacy on NSCLC patients with chronic viral infection, but still has the potential to increase the incidence of hepatitis.