The aim of this study was to assess how often women with undetected calcifications in prior screening mammograms are subsequently diagnosed with invasive cancer. From a screening cohort of 63,895 women, exams were collected from 59,690 women without any abnormalities, 744 women with a screen-detected cancer and a prior negative exam, 781 women with a false positive exam based on calcifications, and 413 women with an interval cancer. A radiologist identified cancer-related calcifications, selected by a computer-aided detection system, on mammograms taken prior to screen-detected or interval cancer diagnoses. Using this ground truth and the pathology reports, the sensitivity for calcification detection and the proportion of lesions with visible calcifications that developed into invasive cancer were determined. The screening sensitivity for calcifications was 45.5%, at a specificity of 99.5%. A total of 68.4% (n = 177) of cancer-related calcifications that could have been detected earlier were associated with invasive cancer when diagnosed. Screening sensitivity for detection of malignant calcifications is low. Improving the detection of these early signs of cancer is important, because the majority of lesions with detectable calcifications that are not recalled immediately but detected as interval cancer or in the next screening round are invasive at the time of diagnosis.