BACKGROUND: Seroma frequently presents as a challenge, following gynecomastia correction surgery. This calls for percutaneous aspiration of accumulated fluid, from the iatrogenic dead space. The authors utilized internal quilting sutures and doxycycline instillation to analyze and compare their roles in seroma prevention. OBJECTIVES: To compare the efficacy of intraoperative internal quilting sutures and doxycycline instillation, in preventing seroma formation and recurrence after gynecomastia surgery. METHODS: After local review board and ethics committee approval, the authors conducted this prospective single-center study of 120 gynecomastia patients with Rohrich's Grades I, II, and III, who underwent surgery between October 2023 and March 2024. Those belonging to Rohrich's Grade IV were excluded. Before surgery, the patients were divided into 3 cohorts of 40 individuals using a computerized randomization protocol. Cohort 1 underwent doxycycline instillation, Cohort 2 underwent internal quilting sutures, and no intervention was carried out in Cohort 3. Seroma diagnosis was confirmed clinically and the data were analyzed. All the patients were followed up for a month. RESULTS: The incidence of seroma formation, volume of seroma fluid removed, and the number of visits for seroma care were statistically found to be the least in the quilting group compared with the doxycycline and control groups. Univariate logistic regression analysis revealed that patients belonging to both doxycycline and control groups showed significantly higher risk for seroma formation with an odds ratio of 4.705 and 6.524, respectively. CONCLUSIONS: Doxycycline instillation was less effective than internal quilting sutures in preventing seroma formation. Internal quilting sutures are a safe effective, and undemanding adjuvant technique to reduce the rate of formation and recurrence of seroma, after gynecomastia surgery.