Background: A contradictory tendency between occurrence of acute respiratory distress syndrome (ARDS) and serum club cell protein 16 (CC16) level, However, renal dysfunction (RD) separately raised serum CC16 in our current observation. The purpose of this study was to find the limitation caused by renal dysfunction in the diagnostic performance of CC16 on ARDS in intensive care unit (ICU) patients. Method: We measured serum CC16 in 479 ICU patients. Patients were divided into six subgroups: control, acute kidney injury (AKI), chronic kidney dysfunction (CKD), ARDS, ARDS+AKI, and ARDS+CKD. The cutoff value, sensitivity and specificity of serum CC16 were assessed by receiver operating characteristic curves. Result: Serum CC16 increased among the ARDS group when compared to the control group, which helps identify ARDS and predicts the outcome in patients with normal renal function. However, level of serum CC16 was similar among ARDS+AKI, ARDS+CKD, AIK and CKD groups. Consequently, when compare to AKI and CKD, specificity for diagnosing whether ARDS or ARDS with renal failure decreased from 86.62% to 2.82% or 81.70% to 2.12%. Consistently, a cutoff value of 11.57 ng/mL was overturned from previously at 32.77 ng/mL or 33.72 ng/mL. Moreover, its predictive value for mortality is prohibited before 7 day but works after 28 day. Conclusion: Renal dysfunction limits the specificity, cutoff point, and predictive value at 7-day mortality of CC16 in diagnosing ARDS among ICU patients.