The oxidation of isobutane at high density of reagents in a mixture of i-C4H10/O2/H2O and i-C4H10/O2/CO2 with oxygen deficiency (a molar ratio [O2]0/[i-C4H10]0 = 3.5–5.8) has been studied for the first time. The experiments were carried out in a tubular reactor under uniform heating (1 K/min) to 590 K. Data on the kinetics, auto-ignition temperature, and the products of isobutane conversion have been obtained. The auto-ignition was found to be a two-stage process and begin at a temperature of 510–522 K. The heat capacity of the reaction mixture suppressed the autoacceleration of the oxidation. Mass spectrometric analysis of the reactants revealed a difference in the mechanisms of isobutane conversion in water vapor and carbon dioxide. In water vapor, the oxidation is dominant and is realized with the participation of vibrationally excited O*2 molecules, which appear mainly from resonant exchange with H2O* molecules. In the CO2 medium, the oxidation proceeds against the background of intense isobutane dissociation, initiated by the vibrational pumping of i-C4H10 molecules in their resonant excitation by CO*2 molecules.