Background: Benign breast diseases (BBD) encompass various non-cancerous conditions affecting breast tissue, often presenting symptoms akin to malignant breast diseases. Management of BBD in seropositive patients, particularly those with chronic viral infections like HIV, poses unique challenges due to immunocompromised states impacting disease course and treatment efficacy. Methods: A prospective randomized controlled study was conducted, enrolling 60 seropositive patients with BBD symptoms. Patients were randomly assigned to receive either ormeloxifene or placebo for 12 weeks. Pain and nodularity scores were assessed using standardized scales, and outcomes were compared between groups. Statistical analyses included descriptive statistics, t-tests, chi-square tests, repeated measures ANOVA, mixed-effects models, and Cox regression. Results: Ormeloxifene demonstrated significant reductions in both pain and nodularity scores compared to placebo. In the ormeloxifene group, pain scores decreased from 7.8 to 2.3 (p < 0.001), while nodularity scores decreased from 3.5 to 1.2 (p < 0.001) over 12 weeks. Compliance with ormeloxifene was high, with minimal reported side effects. The median time to significant improvement was 8 weeks in the ormeloxifene group. Correlation analyses supported the superior efficacy of ormeloxifene over placebo in alleviating BBD symptoms. Conclusion: This study provides robust evidence supporting the efficacy and safety of ormeloxifene in treating BBD in seropositive patients. Ormeloxifene offers a valuable therapeutic option for managing BBD symptoms, particularly in individuals with weakened immune systems. Further research with larger sample sizes and longer follow-up periods is warranted to validate these findings and optimize treatment protocols.