The gas- and aqueous-phase acidities of a series of oxicams have been computed by combining M05-2X/6-311+G(3df,2p) gas-phase free energies with solvation free energies from the CPCM-UAKS, COSMO-RS, and SMD solvent models. To facilitate accurate gas-phase calculations, a benchmarking study was further carried out to assess the performance of various density functional theory methods against the high-level composite method G3MP2(+). Oxicams are typically diprotic acids, and several tautomers are possible in each protonation state. The direct thermodynamic cycle and the proton exchange scheme have been employed to compute the microscopic pKas on both solution- and gas-phase equilibrium conformers, and these were combined to yield the macroscopic pK a values. Using the direct cycle of pKa calculation, the CPCM-UAKS model delivered reasonably accurate results with MAD ∼1, whereas the SMD and COSMO-RS models performance was less satisfactory with MAD ∼ 3. Comparison with experiment also indicates that direct cycle calculations based on solution conformers generally deliver better accuracy. The proton exchange cycle affords further improvement for all solvent models through systematic error cancellation and therefore provides better reliability for the pK a prediction of compounds of these types. The latter approach has been applied to predict the pKas of several recently synthesized oxicam derivatives.