Background: Assessment of kidney function in emergency settings is essential across all medical subspecialties. Daily assessment of patient creatinine result from emergency medical services showed that some creatinine results apparently deviated from expected creatinine values implying occurrence of drug-related interferences. Methods: Real-time head-to-head clinical evaluation of an enzyme method (Roche CREP2) in comparison to Jaffé gen. 2 method (Roche CREJ2) was performed. During the period of December 2022 and January 2023 we analyzed 8498 patient specimens where 5524 were heavily medicated STAT patient specimens, 500 were pediatric specimens and 2474 specimens were from a distant general population in a different region using the same methods. Results: About 5 percent of hospital specimens having patient history showed apparent drops of creatinine concentrations by the enzyme method against the compensated Jaffé method. Suspect medication was found in 43 out of 46 reviewed patients where medication data were allowed for review. A general patient cohort showed no drops of concentrations measured by the enzyme method. Pediatric hospital cohort showed 6 drops out of 500 total measurements. Conclusions: Pharmacotherapy-induced inaccuracies with enzyme creatinine methods imply the need for proper method validations in the relevant patient population such as emergency hospital setting and may facilitate introduction of cystatin C to emergency medicine clinical practice as suitable creatinine alternate biomarker.