Introduction: Cystic fibrosis (CF) is a life-limiting multisystemic genetic disease. Patients with CF have a high rate of hospitalization. We attempt to ascertain national trends of inpatient stays, prevalence of various co-morbidities during hospitalizations, outcomes and discharge disposition among CF patients. Material and methods: Data from the National Inpatient Sample (NIS) was used to identify all hospitalizations of patients with CF and their demographic characteristics from 2003 to 2013. Prevalence and effects of various co-morbidities like acute kidney injury (AKI) were determined. Detailed sub-group analysis was performed for individuals with lung transplant. Results: The annual rate of hospitalization per 1000 CF patients in the U.S. increased from 994 in 2003 to 1072 in 2013. The overall in-hospital mortality was 1.5%; median age at death was 27 years. In-hospital mortality trended down from 1.9% to 1.2% from 2003 to 2013 (p-value for trend: 0.002). The median length of stay was 7 days. The prevalence of chronic liver disease and AKI was 3.7% and 3.8% respectively. Multivariate adjusted odds of mortality for AKI was 1.74 (95% CI 1.57−1.93, p < 0.001). Patients with prior lung transplantation accounted for 6.5% of hospitalizations. These patients had a significantly higher prevalence of AKI. Conclusions: The annual hospitalization rates of CF patients is increasing over the years. Females with CF constitute a higher proportion of hospitalized patients despite a higher male preponderance of males with CF in the community. AKI is associated with a significantly higher in-hospital mortality. Lung transplant recipients have a higher prevalence of AKI and mortality.