Purpose: Introducing the relationship between the surgical instruments used in modified radical mastectomy and wound complications is important for preventing and decreasing complications. This prospective randomized trial was designed to assess the impact of scalpel, electrocautery, and ultrasonic dissector usage on wound complications and tissue damage. Methods: Eighty-two consecutive patients operated with mastectomy were studied. The postoperative time period needed for hemovac drainage, the amount and duration of seroma, infection, flap ecchymosis and necrosis rates were compared. Tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6) levels in drainage fluids were determined to confirm the inflammatory response and tissue damage. Results: The numbers of patients included in the scalpel, electrocautery and ultrasonic dissector groups were 27, 26, and 29, respectively. The groups were homogenous with respect to age, body mass index, stage, cormorbidities, breast volume and flap area. Operation time and the amount of bleeding were statistically higher in the scalpel group. The incidence of seroma was higher in the electrocautery group and arm mobilization had to be delayed in this group. There were no differences between groups with respect to hematoma, infection, ecchymosis, necrosis, hemovac drainage and the total and first 3 days of seroma volume. TNF-a and IL-6 levels were significantly higher in samples obtained from the drains of patients operated with electrocautery. Conclusion: Ultrasonic dissector decreases operation time by decreasing the amount of bleeding without increasing the seroma incidence. High cytokine levels in drainage fluids from patients operated with elecrocautery indicates that electrocautery induces more tissue damage and acute inflammatory response. Therefore, seroma, due to acute inflammatory response, was seen more frequently in the electrocautery group. Ultrasonic dissector coagulates protein by breaking hydrogen bonds which may close vascular and lymphatic channels more precisely. But, its actual preventive effect on seroma formation might be related to diminished inflammatory response.