Background: This population-based study aimed to evaluate trends in surgical approach for screen-detected cancer versus interval breast cancer, and to determine the factors associated with positive resection margins. Methods: Screening mammograms of women aged 50-75 years, who underwent biennial screening in a Dutch breast-screening region between 1997 and 2011, were included. Patient and tumour characteristics were compared between women who underwent mastectomy or breast-conserving surgery (BCS) for screen-detected or interval cancer, and women with a negative or positive resection margin after BCS. Results: Some 417 013 consecutive screening mammograms were included. A total of 2224 screen-detected and 825 interval cancers were diagnosed. The BCS rate remained stable (mean 6.1 per 1000 screened women; P = 0.099), whereas mastectomy rates increased significantly during the study from 0.9 (1997-1998) to 1.9 (2009-2010) per 1000 screened women (P <0 001). The proportion of positive resection margins for invasive cancer was 19.6 and 7.6 per cent in 1997-1998 and 2009-2010 respectively (P <0 001), with significant variation between hospitals. Dense breasts, preoperative magnetic resonance imaging, microcalcifications, architectural distortion, tumour size over 20mm, axillary lymph node metastasis and treating hospital were independent risk factors for mastectomy. Interval cancer, image-guided tumour localization, microcalcifications, breast parenchyma asymmetry, tumour size greater than 20mm, lobular tumour histology, low tumour grade, extensive invasive component and treating hospital were independent risk factors for positive resection margins. Conclusion: Mastectomy rates doubled during a 14-year period of screening mammography and the proportion of positive resection margins decreased, with variation among hospitals. The latter observation stresses the importance of quality control programmes for hospitals treating women with breast cancer.