The purpose of this study was to assess the potential value of tomosynthesis in women with an abnormal screening mammogram or with clinical symptoms. Mammography and tomosynthesis investigations of 513 woman with an abnormal screening mammogram or with clinical symptoms were prospectively classified according to the ACR BI-RADS criteria. Sensitivity and specificity of both techniques for the detection of cancer were calculated. In 112 newly detected cancers, tomosynthesis and mammography were each false-negative in 8 cases (7%). In the false-negative mammography cases, the tumor was detected with ultrasound (n = 4), MRI (n = 2), by recall after breast tomosynthesis interpretation (n = 1), and after prophylactic mastectomy (n = 1). Combining the results of mammography and tomosynthesis detected 109 cancers. Therefore in three patients, both mammography and tomosynthesis missed the carcinoma. The sensitivity of both techniques for the detection of breast cancer was 92.9%, and the specificity of mammography and tomosynthesis was 86.1 and 84.4%, respectively. Tomosynthesis can be used as an additional technique to mammography in patients referred with an abnormal screening mammogram or with clinical symptoms. Additional lesions detected by tomosynthesis, however, are also likely to be detected by other techniques used in the clinical work-up of these patients.