Three-dimensional-conformal radiation (3D-CRT) is the most common approach used in National Surgical Adjuvant Breast and Bowel Project (NSABP) B-39 for accelerated partial breast irradiation (APBI). Administration of APBI-3D-CRT in the preoperative (preop) setting has been shown to decrease the planning target volume. The impact of this decrease on patient eligibility for APBI has not been evaluated in a comparative manner. Forty patients with 41 previously treated breast cancers (≤4 cm) were analyzed. A spherical preop tumor volume was created using the largest reported radiographic dimension and centered within the contoured lumpectomy cavity. Plans were created and optimized using the preop tumor volume and postoperative lumpectomy cavity using NSABP B-39 guidelines. The primary end point was to evaluate for differences in patient eligibility and normal tissue exposure. Thirty-five tumors (85%) in the preop versus 19 tumors (46%) in the postoperative setting were eligible for 3D-CRT-APBI using NSABP B-39 criteria (P=0.0002). The most common reason for ineligibility was due to >60% of the ipsilateral breast volume receiving 50% of the dose. Other reasons included dose to the contralateral breast, heart, and ipsilateral lung. Preop 3D-CRT-APBI was associated with statistically significant improvements in dose sparing to the heart, ipsilateral normal breast tissue, contralateral breast, chest wall, ipsilateral lung, and skin. Dosimetrically, the use of preop radiation would increase patient eligibility for 3D-CRT-APBI and decrease dose to normal tissues, which will potentially decrease toxicity and improve cosmesis. These results provide the basis for a recently activated prospective study of preop 3D-CRT-APBI.