This study examines a couple-based screening protocol for cystic fibrosis (CF) during pregnancy. The screening test is positive only when both partners carry an identifiable mutation. The risk for the fetus to be homozygous is 1 in 4, and definitive prenatal diagnostic testing can be offered. Between six and seven of every ten CF cases can be identified by testing for seven CF mutations. Couple screening for CF has not been evaluated in a decentralized health-care system. Office guides, informational materials, and consent forms were provided to 69 physicians in Maine. Women sent buccal samples to the study centre and brought sampling materials to their partners. Samples from both individuals were required. When a mutation was identified in the woman's sample, the partner's sample was tested. Screening results were reported to the physician. Standardized follow-up surveys were carried out in selected women, key office staff, and physicians. 1770 women and 1682 partners submitted samples. Testing was successfully completed for 1645 couples. Screening results were positive in one couple; the fetus was homozygous for CF. Physicians, office staff, and nearly all women were satisfied with the screening process. Couple screening for CF is feasible and acceptable in decentralized primary care settings.