BACKGROUND: Mammography screening is justifiable only if it leads to reduction in breast cancer mortality. However, evaluation of routine screening is not straightforward, as no unscreened control group is available. We report here on a cohort study of the effect of routine mammography on breast cancer mortality, and illustrate how variations in the analytic approach can affect the conclusions. METHODS: We used data from the mammography screening program in Copenhagen, Denmark, for the period 1991-2001. We used local historical, concurrent regional, and historical regional control groups, and included only deaths from breast cancers diagnosed during the observation periods. We examined the impact of various control groups, of including all breast cancer deaths, and of using individual data versus routine statistics. RESULTS: Combining all 3 control groups gave an estimated 25% reduction in breast cancer mortality. The estimate was 20% using only a local historical control group, and 9% using only a concurrent regional control group. Including all breast cancer deaths resulted in an estimate of 21% reduction in breast cancer mortality. Using routine statistics and a concurrent regional control group resulted in an estimated increase of 6% in breast cancer mortality. CONCLUSION: Estimated changes in breast cancer mortality following the introduction of routine mammography ranged from a 25% reduction (based on the best methodology) to a 6% increase with a less rigid study design. The estimated effect of routine mammography on breast cancer mortality is thus highly dependent on study design.