ObjectiveEstimated glomerular filtration rate (eGFR) calculated by cystatin C (cysC) has been recommended for broader adoption. This study assessed the discrepancy between eGFR calculated by cysC (eGFRcys) and creatinine (eGFRcr) in different patient care settings and explored potential contributing factors to such discrepancies. MethodsThis retrospective study included 2072 patients with paired cysC and creatinine results in different patient care settings. Delta eGFRcr-cys (eGFRcr − eGFRcys) was analyzed in relationship to patient care settings and the Elixhauser Comorbidity index. The 90-day survival in patients with different delta eGFR was assessed by Kaplan-Meier analysis, univariate and multivariate Cox proportional hazard models. In addition, discrepancy between eGFRcys and eGFRcr was analyzed in 50 ambulatory patients with systemic inflammation but normal kidney function. ResultsInpatients had higher cysC (median 1.91 mg/L), lower eGFRcys (median 31 mL/min/1.73 m2), and larger delta eGFRcr-cys (median 18 mL/min/1.73 m2) than outpatients (cysC median 1.53 mg/L, p < 0.0001, eGFRcys median 41 mL/min/1.73 m2, p < 0.0001, delta eGFRcr-cys median 4 mL/min/1.73 m2, p < 0.0001). Higher Elixhauser Comorbidity index correlated with lower eGFRcys and larger delta eGFRcr-cys, with median delta eGFRcr-cys 11 and 6 mL/min/1.73 m2 in patients with a Comorbidity index > 15 and ≤ 15, respectively (p < 0.0001). Increased delta eGFRcr-cys was associated with worse 90-day survival. Patients with systemic inflammation but normal kidney function had lower eGFRcys (median 77.5 mL/min/1.73 m2) than eGFRcr (median 97 mL/min/1.73 m2, p < 0.001), with red blood cell abnormalities as associated factors. ConclusionInflammation and comorbidities are associated with decreased eGFRcys and large discrepancies between eGFRcr and eGFRcys independent of kidney function and are most apparent in inpatients. Creatinine-cysC combined eGFR reduces this discrepancy and should be broadly adopted.