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Despite the frequency and cost of hospitalizations for acute respiratory failure (ARF), the literature regarding the impact of hospital safety net burden on outcomes of these hospitalizations is sparse. ⋯ After accounting for differences between patient cohorts, high safety net burden was associated independently with inferior clinical outcomes and increased costs after ARF hospitalizations. These findings emphasize the need for health care reform to ameliorate disparities within these safety net centers, which treat our most vulnerable populations.