Background: There are phosphatidylinositol-4,5-biphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutations in 30-40% of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2) tumor samples. Nevertheless, clinical outcomes in this group vary amongst research trials. Methods: We sought to determine the incidence of PIK3CA mutations in Bulgarian patients with metastatic HR+, HER2-negative breast cancer, as well as to evaluate and compare progression-free survival (PFS) in the real world between wild-type (WT) and mutant cohorts. In this multicentric retrospective analysis, 250 tissue samples were collected between 2016 and 2022 from three Bulgarian oncology centers. Qualitative real-time PCR was used to determine the existence of PIK3CA mutations. The median follow-up time was 28 months. Results: The mean age was 57.6±11.6 years for the mutant cohort and 56.5±12.2 for the wild-type cohort (p=0.52). The percentage of patients with visceral metastatic disease was 58.8% (n=147). Postmenopausal patients were 84.3% (n=210). PIK3CA mutation prevalence was 29.2% (n=73). The most prevalent mutation was found in exon 20: H1047R (9.2%). Among all clinicopathological features, we observed only a significant relation between the presence of a mutation and a metastatic stage at diagnosis (p = 0.002). 67.1% of the patients received endocrine therapy (ET) + CDK4/6 inhibitor as first-line therapy, while the remainder receive ET monotherapy. Patients with PIK3CA mutation did not have significantly different median PFS compared to WT patients (32 months (95%, CI: 22-40) versus 24 months ((95%, CI: 21-36) (p=0.45)); HR=0.86 (95%, CI: 0.5-1.3) (p=0.46). In propensity matching score analysis (matched for treatment utilized as a first line ET, menopausal status, and locations of metastatic disease), we confirmed our finding (36 months (95%, CI: 20-40) versus 26 months (95%, CI: 21-38), p = 0.69). Conclusions: We demonstrated that the prevalence of PIK3CA mutations in Bulgarian patients is comparable to that reported in other countries. Our findings suggest that the presence of a PIK3CA mutation has no effect on the efficacy of endocrine therapy of first-line treatment. In summary, our study provides valuable insights into the topic, but limitations including the retrospective design and small sample size suggest that the findings need to be replicated by more robust studies and larger sample sizes to draw definitive conclusions.