Purpose To evaluate axis-dependent visual and refractive outcomes of small incision lenticule extraction (SMILE) in patients with interocular astigmatic axis discordance. Methods Seventy-five patients (150 eyes) with interocular astigmatic axis discordance were included in the study. Based on interocular axis combinations, patients were stratified into three cohorts: with-the-rule (WTR)/against-the-rule (ATR) (n = 19), WTR/oblique astigmatism (OA) (n = 39), and ATR/OA (n = 17). Refractive outcomes, corneal topography, and corneal wavefront aberrations were analyzed preoperatively and at 1 and 6 months postoperatively. Vector analysis using the Alpins method compared astigmatic correction accuracy. Results At 6 months, no significant difference was observed in visual acuity or residual sphere or cylinder between axis among different groups. Although 84% of ATR eyes and 64% of OA eyes achieved residual astigmatism of 0.25 diopters (D) or less, compared to 47% and 38% of their contralateral WTR eyes. Vector analysis revealed a systematic undercorrect of correction indices (CI < 1.0) in WTR eyes, and a full correction in non-WTR eyes (ATR CI = 0.99 ± 0.50, OA CI = 1.00 ± 0.47). ATR eyes exhibited greater angle of error compared to the contralateral WTR eyes ( P = .04). OA eyes demonstrated decreased Trefoil30° aberrations compared to the contralateral ATR eyes ( P = .003). Conclusions SMILE exhibited axis-specific efficacy patterns, with predictable astigmatic correction achieved in ATR and OA eyes, whereas WTR eyes demonstrated systematic undercorrection. These findings highlight the clinical relevance of preoperative axis evaluation, particularly in patients with interocular discordance.