The primary analysis (median follow-up 34.9 mo across all arms) of the phase 3 POSEIDON study revealed a statistically significant overall survival (OS) improvement with first-line tremelimumab plus durvalumab and chemotherapy (T+D+CT) versus CT in patients with EGFR and ALK wild-type metastatic NSCLC (mNSCLC). D+CT had a trend for OS improvement versus CT that did not reach statistical significance. This article reports prespecified OS analyses after long-term follow-up (median >5 y).A total of 1013 patients were randomized (1:1:1) to T+D+CT, D+CT, or CT, stratified by tumor cell programmed cell death ligand-1 (PD-L1) expression (≥50% versus <50%), disease stage (IVA versus IVB), and tumor histologic type (squamous versus nonsquamous). Serious adverse events were collected during follow-up.After a median follow-up of 63.4 months across all arms, T+D+CT had sustained OS benefit versus CT (hazard ratio [HR] = 0.76, 95% confidence interval [CI]: 0.64-0.89; 5-y OS: 15.7% versus 6.8%). OS improvement with D+CT versus CT (HR = 0.84, 95% CI: 0.72-1.00; 5-y OS: 13.0%) was consistent with the primary analysis. OS benefit with T+D+CT versus CT remained more pronounced in nonsquamous (HR = 0.69, 95% CI: 0.56-0.85) versus squamous (HR = 0.85, 95% CI: 0.65-1.10) mNSCLC. OS benefit with T+D+CT versus CT was still evident regardless of PD-L1 expression, including patients with PD-L1 tumor cell less than 1%, and remained evident in STK11-mutant (nonsquamous), KEAP1-mutant, and KRAS-mutant (nonsquamous) mNSCLC. No new safety signals were identified.After a median follow-up of more than 5 years, T+D+CT had durable long-term OS benefit versus CT, supporting its use as first-line treatment in mNSCLC, including in patient subgroups with harder-to-treat disease.