OBJECTIVES: To examine the effectiveness and cost-effectiveness of two interventions based in primary care aimed at increasing uptake of breast screening. SETTING: 24 General practices with low uptake in the second round of screening (below 60%) in north west London and the West Midlands, UK. Participants were all women registered with these practices and eligible for screening in the third round. METHODS: Pragmatic factorial cluster randomised controlled trial, with practices randomised to a systematic intervention (general practitioner letter), an opportunistic intervention (flag in women's notes prompting discussion by health professionals), neither intervention, or both. Outcome measures were attendance for screening 6 months after the practices had been screened and cost-effectiveness of the interventions. RESULTS: 6,133 Women were included: 1,721 control; 1,818 letter; 1,232 flag; 1,362 both interventions. Attendance data were obtained for 5,732 (93%) women. The two interventions independently increased breast screening uptake in a logistic regression model adjusted for clustering, with the flag (odds ratio (OR) 1.43, 95% confidence interval (95% CI) 1.14 to 1.79; p=0.0019) marginally more effective than the letter (OR 1.31, 95% CI 1.05 to 1.64; p=0.015). Health service costs per additional attendance were 26 pounds (letter) and 41 pounds (flag). CONCLUSIONS: Although both interventions increased attendance for breast screening, the letter was the more cost-effective. Any decision to implement both interventions rather than just the letter will depend on whether the additional (41 pounds) costs are judged worthwhile in terms of the gains in breast screening uptake.