Objective. To investigate the efficiency and safety of monotherapy with the transdermal micronized progesterone Progestogel for diffuse fibrocystic mastopathy. Materials and methods. The observational study enrolled 722 patients aged 37.1±0.3 years with preserved menstrual function and diagnosed diffuse fibrocystic mastopathy. The observation period consisted of a continuous medication usage period about 3 months (3 cycles), or, if necessary, a second course of as many as 6 months (6 cycles). The main criterion for the efficiency of the therapy was to estimate the number of masses, as evidenced by ultrasonography. During the study, the investigators made breast ultrasound and radiographic examinations, Breast Imaging-Reporting and Data System (BI-RADS) assessment, recorded pain intensity with a visual analogue scale (VAS), and assessed a patient’s health status according to the Clinical Global Impression Scale (CGI). Results. The clinical breast assessment throughout the investigation, by using the main efficiency criterion showed a decrease in the average number of masses in one patient during the treatment: 5.09±0.15 (before treatment), 2.97±0.13 (after 3-month therapy), and 2.29±0.16 (after 6-month therapy), (p < 0.001). There was a significant reduction in the signs of the disease, as assessed by ultrasonography of mass sizes (p <0.001). The changes in the breast detected by its clinical examination and mammography showed statistically significantly better BI-RADS scores (p < 0.001). Pain syndrome intensity assessment using the VAS demonstrated a significant decrease: 47.5±0.8 (before treatment), 13.5±0.6 (following 3 months), and 7.7 ± 0.8 (following 6 months) (p <0.001). Conclusion. The investigation provided evidence for the sufficient efficacy and safety profile of Progestogel monotherapy for fibrocystic mastopathy.