Background: Lung shielding is not standardized during total body irradiation (TBI) preparative regimens for hematopoietic stem cell transplantation (HSCT), leading to differences in pulmonary radiation dose received by patients. We examined the relationship between lung radiation dose and transplant-related mortality (TRM), relapse-free (RFS) and overall survival (OS) in children and adolescents undergoing TBI-based HSCT for acute lymphoblastic leukemia (ALL) on Children’s Oncology Group trial ASCT0431. Methods: The lung radiation dose received during TBI (1200 or1320 cGy given bid in 6 or 8 fractions) was analyzed in relation to the following variables: total TBI dose, TBI dose per fraction, TBI dose rate, TBI fields, patient position during TBI, pulmonary toxicity, acute graft versus host disease (GVHD), veno-occlusive disease (VOD), TRM, donor type, minimal residual disease (MRD) levels, RFS and OS. Results: From a total of 143 enrolled, 109 patients had lung doses available for analysis. Patients treated with lateral fields were significantly more likely to receive lung doses ≥ 800cGy (p < 0.001). Patients receiving lung dose ≥ 800cGy had higher rates of relapse or TRM (p = 0.034), a trend for higher rates of death (p = 0.078). There was no significant association between lung dose and rates of reported pulmonary toxicity (p = 1.000). In univariate analysis, lung dose ≥ 800cGy, grade IV vs. grade I-III GVHD, VOD, pulmonary toxicity, MRD, higher disease risk group and unmatched donor types were associated with significantly inferior RFS and OS. Multivariate analysis identified lung dose ≥ 800cGy to be significantly associated with inferior RFS (HR 1.9; p = 0.031) and OS (HR 2.1; p = 0.023) while controlling for risk group and donor type. Conclusions: Analysis of ASCT0431 data showed that lung irradiation dose ≥ 800 cGy as part of TBI was associated with inferior RFS and OS. While understanding the mechanisms underlying these results requires more research, reducing the lung dose to 800cGy for TBI regimens administering > 1200cGy is recommended. Clinical trial information: NCT00382109