Objective: This pilot study was undertaken to compare radiation dose, relative visibility/conspicuity of biopsy-proven lesions, and relative patient comfort in diagnostic mammography and dedicated cone-beam breast computed tomography (CBBCT) in Breast Imaging-Reporting and Data System (BI-RADS)^® 4 or 5 lesions. Materials and Methods: Thirty-six consecutive patients (37 breasts) with abnormal mammographic and/or ultrasound categorized as BI-RADS^® 4 or 5 lesions were evaluated with CBBCT prior to biopsy. Administered radiation dose was calculated for each modality. Mammograms and CBBCT images were compared side-by-side and lesion visibility/conspicuity was qualitatively scored. Histopathology of lesions was reviewed. Patients were administered a survey for qualitative evaluation of comfort between the two modalities. Results: CBBCT dose was similar to or less than diagnostic mammography, with a mean dose of 9.4 mGy (±3.1 SD) for CBBCT vs. 16.9 mGy (±6.9 SD) for diagnostic mammography in a total of 37 imaged breasts (P<0.001). Thirty-three of 34 mammographic lesions were scored as equally or better visualized in CBBCT relative to diagnostic mammography. Characterization of high-risk lesions was excellent. Patients reported greater comfort in CBBCT imaging relative to mammography. Conclusion: Our experience of side-by-side comparison of CBBCT and diagnostic mammography in BI-RADS^® 4 and 5 breast lesions demonstrated a high degree of correlation between the two modalities across a variety of lesion types. Owing to favorable radiation dose profile, excellent visualization of lesions, and qualitative benefits including improved patient comfort, excellent field-of-view, and more anatomical evaluation of lesion margins, CBBCT offers a promising modality for diagnostic evaluation of breast lesions.