The study described here examined the feasibility of using high-frequency intra-operative ultrasound (hfioUS) guidance to resect superficial intra-cerebral lesions through a single burr hole. A cohort of 23 consecutive patients with a total of 24 intra-cerebral lesions (9 intra-cerebral metastases, 8 gliomas, 4 infections, 2 lymphomas and 1 cavernoma) were studied. All lesions could be localized and successfully resected, biopsied or aspirated, and histopathological diagnoses were obtained in all cases. The mean operating time was 59.6 ± 23.9 min. The mean cross-sectional lesion size was 6.4 ± 7.6 cm(2), and the mean cortex surface-to-lesion distance was 0.6 ± 0.8 cm. Our results illustrate the feasibility of identifying and resecting superficial intra-cerebral lesions under hfioUS guidance via a single-burr-hole approach. We were able to achieve short resection times with no post-operative complications in all patients, favorable conditions under which to start adjuvant therapy when indicated.