Background: The benefit of combination immune checkpoint inhibitor (ICI) with chemotherapy over ICI monotherapy in non-small cell lung cancer (NSCLC) remains underexplored. Methods: This retrospective cohort included patients with metastatic NSCLC from a single-institution database treated with ICI monotherapy or with chemotherapy between 1/2014-2/2020. Clinical progression-free survival (PFS) and overall survival (OS) were the primary outcomes. Propensity score adjustment for clinical and sociodemographic characteristics was used for analysis of first-line treatment outcomes. Results: A total of 1,139 patients (54% male; median age, 64.9) were included. Adenocarcinoma histology, smoking history, higher PD-L1 expression, and lower metastatic stage associated with improved PFS. However, PD-L1 expression and smoking associated with PFS only in adenocarcinoma (LUAD); squamous (LUSC) patients had shorter PFS independent of PD-L1 and smoking history (PD-L1 > 50% vs 1-49%: LUAD P< 0.001; LUSC P = 0.69; Former vs never smoker: LUAD P = 0.008; LUSC P = 0.89). In first-line patients (n = 680), treatment with ICI plus chemotherapy (ICI-chemo) associated with higher progression-free rates at 3 and 6 months compared with ICI-monotherapy (ICI-chemo vs ICI-mono: 3-month PFS, 85.2% vs 68.8%, P = 0.001; 6-month PFS, 66.4% vs 52.6%, P = 0.008). However, there was no difference overall in PFS or OS in either the full or propensity-matched cohort. Treatment with ICI and chemotherapy concurrently vs sequentially was associated with similar PFS (log-rank P = 0.12). Conclusions: In this real-world cohort, the addition of chemotherapy to ICIs may protect against early progression but does not influence long-term outcomes. Treatment with sequential vs concurrent ICI and chemotherapy produced similar outcomes. These findings suggest that combination therapy may maximally benefit patients at risk of early progression.