We have investigated the high-temperature solid-solution strengthening by oxygen in Nb, Nb-Ta and Nb-Mo single crystals by compression tests with constant strain rate. Nb, Nb-20Ta, Nb-40Ta, Nb-20Mo, and Nb-40Mo single crystals with various O content were grown by use of the electron-beam floating zone melting method. It is found that Nb and Nb-Ta single crystals are strengthened by oxygen at temperatures below 1100 K, while Nb-20Mo single crystals are strengthened even at 1473 K. The critical resolved shear stress (c.r.s.s.) of Nb-Ta single crystals at 298 K increases linearly with increasing O content, irrespective of Ta content. Furthermore, the increment of c.r.s.s. of Nb-Ta single crystals is larger than that of Nb. The c.r.s.s. of Nb-Mo single crystals is higher than that of Nb for all temperatures tested, and the c.r.s.s. of Nb-20Mo single crystals also increases with increasing O content. These results indicate that the interstitial-substitutional (i-s) interaction between O and Ta or Mo affects the mechanical properties in the Nb-based alloys at high temperature.