Several studies using a variety of in vitro models indicate that sex hormones such as oestrogen can alter ion transport across epithelial cells by either directly affecting CFTR or altering the activity of alternative chloride channels; such effects may in part explain the gender-difference in disease severity observed in some studies. However, published data are inconsistent with several studies postulating beneficial and others detrimental effects of oestrogen on CF ion transport abnormalities. A large proportion of women with CF regularly use oral contraceptives (OC), but the effect of OC use on disease severity has not been systematically studied. Here, we assessed the effects of OC use in a retrospective study. The data included annual follow-up information from 681 women born between 1937 and 1992 of whom 42% have taken OC for varying periods of time. Data regarding OC use is currently available from 1981 to 2010. We performed an inter-patient analysis comparing average yearly changes in %FEV1 and body mass index (BMI) and total days of intravenous (IV) antibiotic use over a 5-year period between matched cohorts of OC users (n=57), (median age at start of study period: 23 (16–45), median %FEV1 at start of study period: 56.2 (20.4–111.1)), and OC non-users (n=57) (median age at start of study period: 22 (17–44), median %FEV1 at start of study period: 48.4 (12.8–119.6)). We found no differences between the groups (median change in %FEV1: users: −1.87 (−11.5 to 10.4), non-users: −1.03 (−11.8 to 17.9); median change in BMI: users: 0.051 (−1.1 to 1.6), non-users: −0.065 (−1.5 to 3.3); median total days on antibiotics: users: 49 (0–308), non-users: 42 (0–378)). We next performed an intra-patient analysis of the same outcomes over a 3-year period on and a 3-year period off OC in the same patient (n=23–27), but again did not detect any differences in any of the clinical outcomes studied. In conclusion, OC use in CF females did not affect %FEV1, BMI or intravenous antibiotic usage in this study; our findings suggest that there is no evidence of a clinically significant effect on CF outcomes.