BACKGROUND: Previous studies have reported differences in aerobic exercise capacity, expressed as peak oxygen uptake (VO2peak), between people with and without cystic fibrosis (CF) related diabetes (CFRD). However, none of the studies controlled for the potential influence of physical activity on VO2peak. We investigated associations between CFRD and VO2peak following rigorous control for confounders including objectively measured physical activity. METHODS: Baseline data from the international multicenter trial ACTIVATE-CF with participants >/=12 years performing up to 4 h per week of vigorous physical activity were used for this project. Multivariable models were computed to study associations between CFRD and VO2peak (mL.min(-1)) adjusting for a set of pre-defined covariates: age, sex, weight, forced expiratory volume in 1 s (FEV1), breathing reserve index, Pseudomonas aeruginosa infection, and physical activity (aerobic step counts from pedometry). Variables were selected based on their potential confounding effect on the association between VO2peak and CFRD. RESULTS: Among 117 randomized individuals, 103 (52% female) had a maximal exercise test and were included in the analysis. Participants with (n = 19) and without (n = 84) CFRD did not differ in FEV1, physical activity, nutritional status, and other clinical characteristics. There were also no differences in VO2peak (mL.min(-1) or mL.kg(-1).min(-1) or% predicted). In the final multivariable model, all pre-defined covariates were significant predictors of VO2peak (mL.min(-1)), however CFRD [coefficient 82.1, 95% CI -69.5 to 233.8, p = 0.28] was not. CONCLUSIONS: This study suggests no meaningful differences in VO2peak between people with and without CFRD given comparable levels of physical activity.