Introduction Transbronchial lung cryobiopsy (TBLC) is an accepted alternative to surgical lung biopsy (SLB) for diagnosing diffuse parenchymal lung disease (DPLD) that is less invasive and results in comparable diagnostic yields. Performing lung biopsies on hospitalized patients, however, has increased risk due to the patient’s underlying disease severity. Data evaluating the safety and efficacy of TBLC in hospitalized patients are limited. We present a comparison of TBLC for hospitalized and outpatients and provide the safety and diagnostic yields in these populations. Methods Demographic data, pulmonary function values, chest imaging pattern, procedural information, and diagnosis were recorded from enrolled patients. Complications from the procedure were the primary outcomes and diagnostic yield was the secondary outcome. Results 77 patients ( n = 22 hospitalized vs n = 55 outpatient) underwent TBLC during the study period. Comparing adverse events between hospitalized and outpatients revealed no statistically significant differences in pneumothorax (9%, n = 2 vs 5%, n = 3), tube thoracostomy placement (5%, n = 1 vs 2%, n = 1), grade 2 bleeding (9%, n = 2 vs 0%, n = 0), escalation in level of care (5%, n = 1 vs 0%, n = 0), 30-day mortality (9%, n = 2 vs 2%, n = 1), and 60-day mortality (9%, n = 2 vs 4%, n = 2) ( p > 0.05 for all). No deaths were attributed to the procedure. 95% of cases received a multidisciplinary conference diagnosis (hospitalized 100%, n = 22 vs outpatients 93%, n = 51, p = 0.32). Conclusion Our experience supports that TBLC may be a safe and effective modality for acutely ill-hospitalized patients with DPLD. Further efforts to enhance procedural safety and to determine the impact of an expedited tissue diagnosis on patient outcomes are needed.