ABSTRACT Background To compare the treatment outcome and visual prognosis of Vogt-Koyanagi-Harada (VKH) disease presenting as papillitis vs. serous retinal detachment (SRD). Methods Retrospective comparative cohort study of 35 patients with previously unknown VKH diagnosis, followed-up for ≥6 months. Outcomes measured: (1) time to achieve inflammatory control; (2) VKH relapse; (3) ocular complications (glaucoma, sunset glow fundus, cataract, and vision loss ≥2 Snellen lines); and (4) chances for developing a chronic-recurrent disease. Results Females predominated in both groups: 12/16 (75%) papillitis and 18/19 (94.7%) SRD. The mean age at presentation was 29 ± 12 years in the papillitis and 36 ± 14 years in the SRD group (p = 0.119), with an overall median follow-up of 26 months (6–180 months). The papillitis-onset VKH group’s mean time elapsed between symptoms onset and initial treatment was shorter (2.9 ± 1.0 vs. 4.6 ± 2.8 weeks, p = 0.024). Anterior segment inflammation was lower (56% vs. 79%, p = 0.018), requiring a shorter corticosteroids treatment duration (12.8 ± 16.1 vs. 32.7 ± 34.1 months, p = 0.040), achieving an earlier inflammatory control (1.9 ± 0.6 vs. 4.1 ± 3.2 months, p <0.001) with fewer ocular complications (13% vs. 74%, p <0.001), including sunset glow fundus (SGF) (0% vs. 63%, p <0.001). Conversely, SRD-onset VKH was a risk factor for developing disease relapse (HR: 4.53; 95% CI: 1.31–15.69, p = 0.017), ocular complications (OR: 19.60, 95% CI: 3.24–118.50, p = 0.001), and chronic-recurrent disease (OR: 20.63; 95% CI: 2.24–189.84, p = 0.008). Conclusion Mexican-mestizo VKH patients with papillitis-onset VKH disease showed earlier inflammatory control, fewer recurrences, and better visual and ocular complication outcomes.