The CO laser frequency mixing in high-quality ZnGeP2 and GaSe crystals is studied to obtain the 2.15-1 500 μm coherent sources. Secondary Harmonic Generation(SHG), sum- and difference frequency generations are considered as a method for the CO laser frequency mixing and the mode-locking as an efficient way to improve the mixing efficiency.Results show that the internal SHG efficiency of Q-switched multiline CO laser radiation has exceeded by 0.3% for GaSe crystal and has reached by 1.1 % for ZnGeP2 crystal. When the SHG is in ZnGeP2, the internal efficiency of electron beam sustained discharge frequency-tunable mode-locking CO laser is up to 12.5 %. Simultaneous SHG and sum frequency generation show the same output spectrum. It is shown by modeling that the sum and difference frequency generations of neighboring lines of both fundamental and first overtone bands can allow one to get the oscillation,respectively, at 4.0-5.0 μm and 100-≥1 200 μm (THz). In conclusions, the frequency mixing of mode-locked CO laser emission lines in ZnGeP2 crystals allows some one to design 2.15-≥1 500 μm coherent sources with the power frequency conversion efficiency up to or over 12.5%.