Two-photon absorption has been systematically studied in Ca3(VO4)2 and Ca2.7Sr0.3(VO4)2 crystals, both of which are prospective nonlinear optical and laser host materials. A strong dependence of the two-photon absorption coefficients on the orientation of the laser beam polarization with respect to the optical c-axis of the crystals is revealed. The measured coefficients for perpendicular and parallel orientations were 50 ± 10 cm/TW and 19 ± 4 cm/TW in Ca3(VO4)2, and 18 ± 3 cm/TW and 10 ± 2 cm/TW in Ca2.7Sr0.3(VO4)2, respectively. Thus, to minimize optical losses caused by two-photon absorption, an orientation of Ca2.7Sr0.3(VO4)2 crystals with the laser beam polarization parallel to the crystal optical c-axis is preferred.