In order to obtain new insights into the relevance of inhibitors in whole urine by focusing on their reciprocal interactions, a statistical approach was followed in 35 controls and 27 calcium oxalate stone formers. The results show that the urinary inhibiting activity (UIA) is significantly higher in stone formers than in controls. The UIA is mainly due to the presence of a protein inhibitor, which is not present in the urine of controls. The protein inhibitor is identified as a 30 kDa protein, which is also present in the urine of patients with kidney stones. The results suggest that the protein inhibitor may play a role in the formation of kidney stones. The study also shows that the UIA is not correlated with the urinary excretion of calcium oxalate, suggesting that the protein inhibitor may be involved in the inhibition of calcium oxalate crystallization rather than in the inhibition of calcium oxalate precipitation. The study provides new insights into the role of inhibitors in the formation of kidney stones and suggests that the protein inhibitor may be a useful marker for the diagnosis of kidney stone disease.