High-level ab initio and density functional theory calculations have been used to investigate the relationship between pK(a) mismatch and hydrogen bond strength in a typical low-barrier hydrogen bond system. It is found that a difference of 1 pK(a) unit between the pK(a) values of the two substituted formate anion＇s vying for a proton in the substituted formic acid-formate anion complex will result in a weakening of the corresponding hydrogen bond by approximately 1.8 kcal/mol. This suggests that small differences in pK(a) values (i.e. 1-2 pK(a) units) of proton donors and proton accepters in enzyme active sites should not preclude the importance or significance of LBHBs during the reactions catalyzed by many enzymes. On the other hand, larger differences in relative pK(a) values ton the order of 5-6 pK(a) units) should be sufficient to cause a considerable weakening of any purported SSHB that might be formed during such an enzyme reaction. It is thus concluded that, just as Gerlt and Gassman suggested in their original paper on LBHBs fmd enzyme catalysis,(8a) the pK(a) matching within the enzyme active site of the two species involved in the LBHB is important to maximizing catalytic stabilization.