PurposeImprovements in molecular breast imaging (MBI) have increased the use of MBI as adjunct diagnostic modality and alternative to MRI. We aimed to assess the value of MBI in patients with equivocal breast lesions on conventional imaging, especially in terms of its ability to rule out malignancy.MethodsWe selected patients who underwent MBI in addition to conventional diagnostics due to equivocal breast lesions between 2012 and 2015. All patients underwent digital mammography, target ultrasound and MBI. MBI was performed using a single-head Dilon 6800 gamma camera after administration of 600 MBq99mTc-sestamibi. Imaging was reported according to BI-RADS classification and compared with pathology or follow-up of ≥6 months.ResultsOf 226 women included, pathology was obtained in 106 (47%) and (pre)malignant lesions were found in 25 (11%). Median follow-up was 5.4 years (IQR 3.9–7.1). Sensitivity was higher for MBI compared to conventional diagnostics (84% vs. 32%;P= 0.002), identifying malignancy in 21 and 6 patients, respectively, but specificity did not differ (86% vs. 81%;P= 0.161). Positive and negative predictive value were 43% and 98% for MBI and 17% and 91% for conventional diagnostics. MBI was discordant with conventional diagnostics in 68 (30%) patients and correctly changed diagnosis in 46 (20%) patients, identifying 15 malignant lesions. In subgroups with nipple discharge (N= 42) and BI-RADS 3 lesions (N= 113) MBI detected 7 of 8 occult malignancies.ConclusionMBI correctly adjusted treatment in 20% of patients with diagnostic concerns after conventional work-up, and could rule out malignancy with a high negative predictive value of 98%.