The advances in imaging techniques and growing awareness have increased the detection of nonpalpable breast lesions, which may be neoplastic or high-risk lesions. The standard technique of localizing these nonpalpable breast lesions is wire-guided biopsy/lumpectomy. However, wire-guided excision is fraught with the complications of migration, transection, patient discomfort, pneumothorax, vasovagal episodes, and injury to the radiologist, surgeon, and pathologist. We embarked upon a randomized controlled trial to compare the cost-effectiveness and patient-reported outcome (PRO) with hematoma-directed ultrasound-guided lumpectomy (HDUGL) versus conventional wire-guided lumpectomy (WGL) for nonpalpable breast lesions. This study was a parallel design, randomized controlled trial with a superiority hypothesis. Twenty-five patients could be randomized to wire-guided lumpectomy (WGL) group (n = 13) and hematoma-directed ultrasound-guided lumpectomy (HDUGL) group (n = 12). Post-excision specimen sonography and mammography for assessing adequacy of margin were done. A margin shave was performed in cases of close or suspicious margin on ultrasonography or mammogram. Both the groups were comparable in age, tumor size, histological subtypes, and location of lesions. The median resection volume in two groups was 34.5 (26.5) ml for HDUGL vs. 41 (15) ml for WGL. Intraoperative cavity shave was required only in the WGL group (n = 3.23%) and margin positivity was also more in the WGL group (n = 2,15.38%) as compared to the HDUGL group (n = 1,8.33%) but neither differences in cavity shave nor positive margins leading to re-operations were statistically significant. The difference in cost of surgery in two groups (INR 4680 ± 560.00 for HDUGL and INR 7486 ± 616.41 for WGL) was statistically significant (P = 0.00). Resultantly, HDUGL was more cost-effective (INR 5105.45) than WGL (INR 8847.09). Patients in the HDUGL group were more satisfied according to the Likert scale of 5 but this difference in two groups was not statistically significant (P = 0.07). The hematoma-directed ultrasound-guided lumpectomy (HDUGL) is better than wire-guided lumpectomy (WGL) for nonpalpable breast lesions in terms of cost-effectiveness. Trial details: CTRI No. CTRI/2019/05/019347. Registered on 24/05/2019, Registered prospectively.