Abstract: Stereotactic biopsy has proven more cost effective for biopsy of lesions associated with moderately suspicious mammograms. Data regarding selection of stereotactic biopsy (CORE) instead of excisional biopsy (EB) as the first diagnostic procedure in patients with nonpalpable breast lesions and highest suspicion breast imaging-reporting and data system (BI-RADS)-5 mammograms are sparse. Records from a regional health system radiology database were screened for mammograms associated with image-guided biopsy. A total of 182 nonpalpable BI-RADS-5 lesions were sampled in 178 patients over 5 years, using CORE or EB. Initial surgical margins, number of surgeries, time from initial procedure to last related surgical procedure, and hospital and professional charges for related admissions were compared using chi-squared, t-test, and Wilcoxon Mann–Whitney tests. A total of 108 CORE and 74 EB were performed as the first diagnostic procedure. Invasive or in situ carcinoma was diagnosed in 156 (86%) of all biopsies, 95 in CORE and 61 in EB groups. Negative margins of the first surgical procedure were more frequent in CORE (n = 70, 74%) versus EB (n = 17, 28%), p < 0.05. Use of CORE was associated with fewer total surgical procedures per lesion (1.29 ± 0.05 versus 1.8 ± 0.05, p < 0.05). Time of initial diagnostic procedure to final treatment did not vary significantly according to group (27 ± 2 days versus 22 ± 2 days, CORE versus EB). Mean charges including the diagnostic procedure and all subsequent surgeries were not different between CORE and EB groups ($10,500 ± 300 versus $11,500 ± 500, p = 0.08). Use of CORE as the first procedure in patients with highly suspicious mammograms is associated with improved pathologic margins and need for fewer surgical procedures than EB, and should be considered the preferred initial diagnostic approach.