ObjectivesThe appropriate holistic management is mandatory for successful endoscopic ultrasound (EUS)‐guided treatment of pancreatic fluid collections (PFCs). However, comorbidity status has not been fully examined in relation to clinical outcomes of this treatment.MethodsUsing a multi‐institutional cohort of 406 patients receiving EUS‐guided treatment of PFCs in 2010–2020, we examined the associations of Charlson Comorbidity Index (CCI) with in‐hospital mortality and other clinical outcomes. Multivariable logistic regression analysis was conducted with adjustment for potential confounders. The findings were validated using a Japanese nationwide inpatient database including 4053 patients treated at 486 hospitals in 2010–2020.ResultsIn the clinical multi‐institutional cohort, CCI was positively associated with the risk of in‐hospital mortality (Ptrend < 0.001). Compared to patients with CCI = 0, patients with CCI of 1–2, 3–5, and ≥6 had adjusted odds ratios (95% confidence intervals) of 0.76 (0.22–2.54), 5.39 (1.74–16.7), and 8.77 (2.36–32.6), respectively. In the nationwide validation cohort, a similar positive association was observed; the corresponding odds ratios (95% confidence interval) were 1.21 (0.90–1.64), 1.52 (0.92–2.49), and 4.84 (2.63–8.88), respectively (Ptrend < 0.001). The association of higher CCI with longer length of stay was observed in the nationwide cohort (Ptrend < 0.001), but not in the clinical cohort (Ptrend = 0.18). CCI was not associated with the risk of procedure‐related adverse events.ConclusionsHigher levels of CCI were associated with a higher risk of in‐hospital mortality among patients receiving EUS‐guided treatment of PFCs, suggesting the potential of CCI in stratifying the periprocedural mortality risk.Trial registrationThe research based on the clinical data from the WONDERFULcohort was registered with UMIN‐CTR (registration number UMIN000044130).