Purpose: To compare clinical outcomes of wavefront-optimized (WFO) and wavefront-guided (WFG) photorefractive keratectomy (PRK) in patients with moderate-to-high astigmatism. Methods: Patients with corneal cylinder above 2 diopters and myopic spherical equivalent were randomized into WFO or WFG PRK. Visual acuity (VA), refraction, contrast sensitivity, higher-order aberrations (HOAs), and astigmatic vector differences were documented and compared for 6 months after surgery. Results: The total number of 362 eyes from 181 patients was analyzed. The amount of total aberration was reduced 2.7 root mean square (RMS) and 2.9 RMS in the WFO and WFG groups, respectively ( P < 0.001 in each group and between the groups). HOAs including coma, trefoil, and spherical aberrations increased in both the groups ( P < 0.001) but were significantly more in the WFO group ( P < 0.001). The increased spherical aberration was similar in both the groups ( P = 0.12). Surgically induced astigmatism was not significantly different between the groups ( P = 0.20). The magnitude of error was significantly higher in the WFO group ( P < 0.001), but the absolute angle of error and the arithmetic angle of error were not significantly different between the groups ( P = 0.20 and P = 0.30, respectively). Conclusion: WFO and WFG platforms of PRK appear comparable in terms of VA, refractive correction, and total aberration. Yet, HOAs may increase especially after WFO PRK.