Abstract: The present invention describes methods and compositions comprising new protease inhibitor stabilizers of brain natriuretic peptide (BNP), which prevent or significantly reduce the degradation of BNP in blood based samples, particularly plasma samples. The BNP inhibitors of the invention include D-Phe-Phe-Arg-chloromethylketone (PPACK), D-Phe-Pro-Arg-chloromethylketone (PPRACK), acetyl-Leu-Leu-arginal (leupeptin), N-(N&agr;-carbonyl-Arg-Val-Arg-al)Phe (antipain) and diisopropylfluorophosphate (DFP), either alone or in combination. The inhibitors, and combinations thereof, can be directly added to collected blood samples prior to testing in laboratory or clinical settings. In addition, the inhibitors, alone or in combination, can be added to blood-based (e.g., plasma) matrices prior to, or at the time of, the addition of exogenous BNP (e.g., synthetic BNP), to prepare control materials used in BNP analysis and quantification of patient blood samples.