By using a multilayer composite ab initio method ONION-G3B3, we calculated O-H bond dissociation enthalpies (BDEs) of 58 oximes that were measured experimentally. Experimental BDEs derived from thermal decomposition kinetics and calorimetric measurements were found to be consistent with the theory. However, the electrochemical method was found to give questionably high BDEs possibly due to errors in the measurement of pK(a)'s or redox potentials. Subsequently, the performances of a variety of DFT functionals including B3LYP, B3P86, B3PW91, BHandH, BHandHLYP, BMK, PBE1PBE, MPW1KCIS, mPWPW91, MPW1B95, and MPW1K were tested to calculate oxime O-H BDEs, where ROBHandHLYP was found to be the most accurate. By using this method, we calculated O-H BDEs of over 140 oximes in a systematic fashion. All of the calculated O-H BDEs fell in the range from 76.8 to 89.8 kcal/mol. An amino group on the azomethine carbon was found to strengthen the O-H bond, whereas bulky alkyl substituents on oximes decreased O-H BDEs due to their large steric-strain-relieving effects in the process of O-H bond cleavage. Para substituents had little effect on the BDEs of benzaldoximes and phenyl methyl ketoximes. Finally, on the basis of a spin distribution calculation, aryl-, alkyl-, and carbonyl-substituted iminoxyl radicals were found to be sigma-radicals, whereas amino-substituted iminoxyl radicals were of pi-structure.