Background Rituximab based chemotherapy regimens, particularly R-CHOP, are highly effective for the treatment of B-cell lymphoma (BCL) but are frequently complicated by pulmonary adverse effects (PAEs) that may disrupt therapy and adversely affect outcomes. This prospective study evaluated whether adjunctive thymosin alpha 1 (Thα1) combined with intravenous immunoglobulin (IVIG) reduces RCHOP associated pulmonary toxicity and improves survival.Methods In this prospective cohort study, 379 patients with histologically confirmed BCL and no pre-existing respiratory disease received R-CHOP therapy between February 2008 and October 2019 and had no prior history of respiratory disease. Exclusion criteria were primary pulmonary pathology, significant comorbidities, and pregnancy or lactation. Participants received either standard R‑CHOP alone (n = 164) or R‑CHOP plus adjunctive Thα1‑IVIG (n = 215), initiated 8–10 days after rituximab administration. The primary endpoint was the incidence of PAE. Secondary endpoints included infectious pulmonary events (IP), interstitial pulmonary disease (IPD), and 5‑year event‑free survival (EFS). Multivariable Cox proportional hazards models were used to identify independent risk and protective factors.Results Among 379 patients, the Thα1-IVIG therapy was associated with a significantly lower overall PAE (13.0% vs. 31.7%, P < 0.001) and IP (4.2% vs. 19.5%, P < 0.001), whereas the incidence of IPD was not significantly different (8.8% vs. 12.2%, P = 0.286) between the two groups. Five‑year event-free survival (EFS) was higher in the Thα1‑IVIG group (77.7% vs. 61.0%, P < 0.001). Multivariate modeling identified extra nodal involvement as a risk factor for PAEs (HR = 1.79, 95% CI 1.14–2.82, P = 0.011), and Thα1‑IVIG therapy appeared to be independently protective (HR = 0.40, 95% CI 0.25–0.64, P < 0.001).Conclusion Thα1-IVIG prophylaxis is a safe, and cost-efficient strategy to reduce pulmonary toxicity, improve treatment adherence and improvement EFS in patients receiving R-CHOP.