To investigate whether the degree of astigmatism axis discrepancy between preoperative manifest refractive astigmatism and anterior corneal astigmatism impacts refractive and visual outcomes of primary topography-guided laser in situ keratomileusis (LASIK) targeting the refractive astigmatism, and to provide guidance on treating eyes with very large axis discrepancy. Comparative retrospective analysis of 25,396 consecutive eyes treated with topography-guided LASIK on the manifest refractive astigmatism. Standard outcomes of the 14,534 eyes with small axis discrepancy (SAD) (Δ in axis ⩽ 10°) were compared to the 2,222 eyes with very large axis discrepancy (VLAD) (Δ in axis ⩾ 45°). Pearson correlation coefficient was used to assess relationships between selected variables. The mean axis discrepancy was 4.47 ± 2.92° in SAD eyes, and 65.0 ± 13.4° in VLAD eyes. An equivalent number of eyes achieved a cumulative postoperative unilateral uncorrected distance visual acuity of 20/20 in both the SAD and VLAD groups (93.02% vs 93.42%; P = .4892). The efficacy index (0.98 ± 0.13 vs 0.98 ± 0.07; P = .3931) and the safety index (1.00 ± 0.11 vs 1.00 ± 0.03; P = .4757) were identical between groups. There was no clinically meaningful correlation between the preoperative axis discrepancy and preoperative total root mean square anterior corneal coma, postoperative refractive astigmatism, defocus equivalent, spherical equivalent, and angle of error, all with weak correlation coefficients (R = -0.02, -0.03, -0.02, 0.01, and 0.05). Large preoperative axis discrepancy (45° to 90°) between refractive astigmatism and topography-measured anterior corneal astigmatism does not negatively impact topography-guided LASIK, having identical refractive and visual outcomes compared to eyes with small (0° to 10°) discrepancy. There is no basis to exclude eyes with large axis discrepancy from topography-guided LASIK, and these eyes should be treated on the manifest refractive astigmatism. [J Refract Surg. 2021;37(10):662-673.].