DESIGN: An extended age-period-cohort model was used to estimate the effect of mammographic screening and hormone replacement therapy on breast cancer incidence in England and Wales between 1971 and 2001. RESULTS: Incidence of breast cancer increased noticeably in women attending screening for the first time compared with nonattenders [rate ratio (RR), 1.73; 95% confidence interval (95% CI), 1.67-1.80]. Incidence was also 18% to 35% higher in attenders relative to nonattenders in subsequent screening rounds. In the first 3 years after women left the screening program, rates of breast cancer were reduced (RR, 0.88; 95% CI, 0.86-0.90), but by 7 to 9 years after screening, the rates had returned to the expected level (RR, 0.97; 95% CI, 0.94-1.00). The estimated RR of hormone replacement therapy on breast cancer incidence was 1.55 (95% CI, 1.37-1.75). Screening is estimated to increase a woman's lifetime risk of being diagnosed with breast cancer from 7.8% to 8.6%. CONCLUSIONS: It is estimated that in the absence of screening, rates of breast cancer incidence would have continued to increase. A study at the individual subject level would be beneficial to assess the level of overdiagnosis associated with breast cancer screening.