Comparable low nanoparticle production is a weakness of femtosecond-pulsed laser ablation in liquids, but the process ablation rate can be maximized at optimal focusing conditions and liquid levels. Refraction at the air−liquid boundary, vaporization of the liquid, self-focusing, and optical breakdown in the liquid complicate the determination of these optimal parameters. A semiempirical method has been developed, allowing an a priori determination of the appropriate experimental setup (liquid layer over the target, focal length, and lens position) for efficient ablation. The presented work can be applied with high accuracy for tightly focused beams, whereas loosely focused ultrashort lasers should be avoided to induce effective fabrication of colloids via laser ablation in liquids.