Objective: Mutations in Mediator Complex Subunit 12 (MED12) gene are typical genomic aberrations, commonly detected in a high percentage of uterine leiomyomas (ULs). The aim of this investigation was to define the fibroid or non-tumor origin of uterine leiomyoma pseudocapsule (PC) surrounding fibroids and its possible therapeutic targets in uterine fibroid management. Research design and methods: A non-randomized observational study was performed on 36 women, not subjected to any previous drug treatment, undergoing laparoscopic intracapsular myomectomy. Specimens of myometrium (UM), ULs and corresponding PCs were sampled to analyze MED12 gene status, by direct sequencing of exon 2. Main outcome measures: Defining the status of MED12 gene in PCs associated to ULs harboring mutations. Results: PCs always showed a wild type MED12 gene status, even when associated to a UL harboring a specific MED12 aberration. Conclusion: The wild-type status of MED12 gene in the PCs indicates the non-tumoral origin of this structure: it appears as a protective structure for the healthy tissue that could enhance regenerative mechanisms. The limitations of this study, as the restrained number of patients, will be solved in the future extending the analysis to a larger cohort of women, as tester of such pharmacological treatments on PC.