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Patients with psoriasis commonly opt for homeopathic treatment. However, no study has assessed the response to homeopathic treatment by using standardized disease-specific scales, and the findings are based on clinical assessments only. The objective of this study was to evaluate the response to the individualized homeopathic treatment of psoriasis with respect to changes in disease severity and quality of life based on Psoriasis Area and Severity Index (PASI) and Psoriasis Disability Index (PDI) scales, respectively. A multicentric study was conducted using a pragmatic model. The study participants were regularly followed up for 1 year. Subsequently, participants completing the 1-year follow-up were included in a long-term assessment for further 2 years. Three monthly assessments were made by using PASI, PDI, and Visual Analog scales for patient and physician general assessment. Data were analyzed to identify treatment effects and variables affecting treatment. In total, 384 patients were enrolled, out of whom 254 participants completed 1 year of treatment. Of these, 84 participants continued treatment for an additional 12 months. A significant reduction was observed in the scores of PASI (10.96 ± 10.67 at baseline to 4.24 ± 5.10 at 12 months, p = 0.000), PDI (10.19 ± 9.11 to 3.91 ± 4.44, p = 0.000), and patient and physician global assessment scales. Regarding PASI response at 12 and 24 months, PASI 75–89 was reported in 66 and 14 participants, whereas PASI 90–100 was reported in 29 and 17 participants, respectively. Baseline severity of psoriasis considerably affected treatment response, whereas age, gender, and duration of psoriasis did not. Furthermore, the severity of psoriasis and quality of life improved considerably with regular homeopathic treatment.