This study examines the influence of work-up on the accuracy of diagnostic mammography in symptomatic women. Subjects were sampled from all women consecutively attending a symptomatic breast clinic and aged 25-55 years (240 women shown to have breast cancer and 240 age-matched women shown not to have cancer). Mammography films were prospectively reported by two radiologists independently of each other and in a blinded manner using two phases of film reading: initially only baseline films were read, then mammography was re-read with work-up films. The accuracy of reporting mammography with and without work-up was compared using sensitivity and specificity, likelihood ratios, and receiver operating characteristic (ROC) curves. Reporting the mammogram with work-up (compared to without any work-up films) improved sensitivity (75.3% vs 69.0%, P=0.059) for one radiologist, with a non-significant gain in specificity (84.5% vs 79.4%, P=0.38). For the other radiologist, it resulted in a non-significant decrease in sensitivity (79.5% vs 83.7%, P=0.14) with a significant increase in specificity (85.6% vs 61.9%, P=0.00001). ROC curves for both radiologists showed that reporting mammography with work-up resulted in significant improvement (4.5% for R1, 6.8% for R2) in overall test accuracy. Our findings support the use of work-up mammography in the diagnostic setting.