Objective: To perform a rigorous comparative evaluation of stepwise and couple approaches to antenatal carrier screening for cystic fibrosis. Design: Pragmatic randomised trial. Setting: Hospital antenatal clinic serving a regional population. Subjects: 2002 women (couples) attending for booking antenatal visit at less than 17 weeks' gestation with no family history of cystic fibrosis. Interventions: Offering counselling and carrier testing for cystic fibrosis, either to women in the first instance (stepwise) or to couples (couple screening). Main outcome measures: Uptake rates; anxiety; knowledge of cystic fibrosis and carrier status (both partners); attitudes to health, pregnancy, the baby, and screening (both partners); and uptake of carrier testing by relatives. Results: Uptake of screening was the same for both approaches (90%). After delivery most women remembered test results and their meaning, but 53/253 (21%) of those with negative results of couple testing had forgotten that repeat testing would be advisable if they had a pregnancy with a new partner. With stepwise screening women identified as carriers had high levels of anxiety when results were received (mean anxiety score 52.3). This dissipated with a reassuring partner's result (carriers' mean anxiety score 36.1) to levels similar to those receiving negative results from couple screening. Of those receiving negative results, women who had stepwise screening were significantly less anxious than those who had couple screening (mean score with result 32.1 v 35.4, 95% confidence interval for difference −4.7 to −2.1). Conclusions: Couple screening allows carriers to avoid transient high levels of anxiety, but is associated with more anxiety and false reassurance among most screenees who will test negative. Stepwise screening gives carriers and their relatives genetic information and is, in our opinion, the better method. Key messages This study compares the stepwise and couple approaches to antenatal screening for carriers of cystic fibrosis With stepwise screening carriers experience transiently high levels of anxiety that dissipate when the partner's negative result becomes available Carriers identified by stepwise screening inform most of their siblings about their genetic risk Couple screening is associated with more anxiety and more false reassurance among most screenees, who will have negative results On balance, the authors judge stepwise screening to be the better method.