Purpose: The aim of this study was to evaluate changes in breast tumor bed volume during whole breast irradiation (WBI). Materials and Methods: From September 2011 to November 2012, thirty patients who underwent breast-conserving surgery (BCS) followed by WBI using computed tomography (CT) simulation were enrolled. Simulation CT scans were performed before WBI (CT1) and five weeks after the breast irradiation (CT2). The tumor bed was contoured based on surgical clips, seroma, and postoperative change. We retrospectively analyzed the factors associated with tumor bed volumetric change. Results: The median tumor bed volume on CT1 and CT2 was 29.72 and 28.6 mL, respectively. The tumor bed volume increased in 9 of 30 patients (30%) and decreased in 21 of 30 patients (70%). The median percent change in tumor bed volume between initial and boost CT was -5%. Seroma status (p = 0.010) was a significant factor in tumor bed volume reduction of 5% or greater. However, patient age, body mass index, palpability, T stage, axillary lymph node dissection, and tumor location were not significant factors for tumor bed volumetric change. Conclusion: In this study, volumetric change of tumor bed cavity was frequent. Patients with seroma after BCS had a significant volume reduction of 5% or greater in tumor bed during breast irradiation. Thus, resimulation using CT is indicated for exquisite boost treatment in breast cancer patients with seroma after surgery.