SCT indications and procedures are increasing worldwide. We sought to estimate the prevalence of acute respiratory failure (ARF) of any cause in hospitalized SCT patients, and assess the impact of invasive mechanical ventilation (IMV) on outcomes. We hypothesize that duration of IMV in such patients is an independent predictor of higher mortality. We performed a retrospective analysis of the largest all-payer hospitalization data set in the United States, Nationwide In-patient Sample for years 2004-2010. Of the 101 462 SCT hospitalizations, 6074 (6%) developed ARF and were the final cohort. Type of SCT with ARF included autologous 1987 (32.7%), allogeneic 3467 (57.1%) and cord blood 655 (10.8%). Duration of IMV included <96 h (17.1%) and ⩾96 h (41.1%). Overall in-hospital mortality (IHM) was 50.6% (3075). Predictors of IHM were IMV <96 h (odds ratio=3.42 (2.44-4.79), P<0.0001) or IMV ⩾96 h (OR=4.61 (3.17-6.70), P<0.0001). Type of SCT, comorbid burden, gender, hospital-teaching status/bed size or insurance did not influence IHM. IMV ⩾96 h was associated with higher hospital charges (mean $762 515, 95% estimate 0.3991 (0.3123-0.4859), increase of $304 474, P<0.0001) and higher length of stay (mean 61.5 days, 95% estimate 0.2198 (0.1531-0.2866), increase of 13 days, P<0.0001). In conclusion, ARF in hospitalized SCT patients is not an uncommon occurrence and is associated with 50% mortality. Duration of IMV (⩾96 h) was an independent predictor of higher mortality rates. Hospital resource utilization was significant.