Background: Ixekizumab, an IL-17A inhibitor, is an effective treatment for moderate-to-severe plaque psoriasis. Although clinical trials support the use of an induction phase for optimal results, real-world evidence comparing induction versus maintenance-only regimens is limited. Objectives: This study assessed the real-world effectiveness, safety, and drug survival of ixekizumab with and without an induction phase in patients with moderate-to-severe plaque psoriasis. Methods: A multicenter, observational study was conducted with 183 patients treated with ixekizumab over five years at tertiary hospitals in Andaluc & iacute;a, Spain. Patients were divided into two groups: an induction group (160 mg at baseline, followed by 80 mg at weeks 2, 4, 6, 8, 10, and 12, then every 4 weeks) and a non-induction group (80 mg every 4 weeks from initiation). Baseline characteristics, clinical outcomes (PASI [Psoriasis Activity Skin Index] and PGA [Physician Global Assessment] scores), and drug survival were analyzed. Results: The majority of patients were male (64.48% in the induction group, 58.74% in the non-induction group). No significant differences were found in age or BMI [body mass index] between groups. Baseline PASI and PGA scores were higher in the induction group, reflecting greater initial disease severity. Both regimens achieved significant clinical improvements, though the induction group demonstrated faster initial responses. Drug survival was lower in the induction group (p = 0.0033), potentially due to the higher baseline disease burden and severity in these patients. Comorbidities, including metabolic syndrome, cardiovascular risks, and psychiatric conditions, were prevalent, particularly in the induction group. Conclusions: Ixekizumab is effective for moderate-to-severe plaque psoriasis, with induction therapy yielding faster responses. However, lower drug survival in the induction group highlights the influence of initial disease severity on long-term outcomes. Real-world findings support the flexibility of ixekizumab across diverse patient populations, though further research is warranted.