This work reports the effect of oxygen activity on surface segregation for TiO2 co-doped with two cations, indium and niobium (0.076 at.% In + 0.103 at.% Nb). In this work, we studied the effect of annealing at 1273 K in the gas phase of controlled oxygen activity on surface segregation of both ions. The applied oxygen activity included pure oxygen, p(O-2) = 100 kPa, and argon, p(O-2) = 10 Pa. The segregation-induced concentration gradients were determined using both secondary ion mass spectrometry and X-ray photoelectron spectroscopy. The obtained results indicate that annealing of the studied TiO2 specimens in argon results in cooperative segregation of both ions leading to the formation of a surface structure involving comparative concentrations of both cations. However, annealing in oxygen results in preferential segregation of indium leading to the formation of a In2TiO5-type surface structure. The obtained results are considered in terms of the effect of multicomponent segregation on processing of the surface layer with controlled properties that are desired for specific applications. The present work indicates that oxygen activity may be used as the parameter in surface engineering of the solid solution.