Objective(s) To determine the association of Clostridioides difficile Infection (CDI) with in‐hospital mortality, Length of Stay (LOS), and hospital charges among pediatric Cystic Fibrosis (CF) hospitalizations using a large nationally representative pediatric hospital database. Study design We identified Cystic Fibrosis‐related hospitalizations during the years 1997 to 2016 in the Kids' Inpatient Database (KID) and compared in‐hospital mortality, LOS, and hospital charges among hospitalizations with and without a coexisting diagnosis of C. difficile using logistic regression models for mortality and general linear models with gamma distribution and logarithmic transformation for LOS and hospital charges. We also evaluated temporal trends in the proportion of CF hospitalizations with concomitant CDI using data published triennially Results We analyzed 21,616 pediatric CF hospitalizations between the years 1997 to 2016 and found a total of 240 (1.1%) hospitalizations with concurrent CDI diagnosis. Adjusted analyses demonstrated an association of CDI with increased mortality (OR 5.2, 95% CI 2.5–10.7), longer LOS (46.5% increment, 95% CI 36.0–57.1), and higher charges (65.8% increment, 95% CI 53.5–78.1) for all comparisons. The proportion of CF hospitalizations with CDI increased over time from 0.64% in 1997 to 1.73% in 2016 (p < 0.001). Conclusion(s) As CDI is associated with excess mortality, LOS, and cost in children hospitalized for CF, a healthy level of suspicion for CDI may be needed in patients with CF in the appropriate clinical context. Efforts to prevent, diagnose, and treat CDI may improve hospital outcomes among children with CF.