To assess risks for parental depression following the diagnosis of cystic fibrosis (CF) in a child. Study design Matched cohort study in NW England; 45 parental couples with a child diagnosed with CF were compared with 45 control couples matching for age, sex, and position in the family of the index child. The Beck Depression Inventory (BDI-II) with a clinical cut-off ≥13 for dysphoria (mild depression) was the main outcome. A stratified analysis was conducted using the Mantel-Haenszel risk-ratio estimator (RRMH) with eight strata for each of the matching variable combinations. Results Heterogeneity was found within the dataset. Parents with a child with CF ≤9 months of age at baseline had an elevated prospective risk of depression (mothers RRMH [95% confidence interval(CI)] = 2·6[1·05,6·42], fathers RRMH [95%CI] = 2·26 [0·97,5·28]). The absence of a group effect for depression at follow-up after adjusting for the matching (mothers RRMH [95%CI] = 1·1 [0·59,2·05], fathers RRMH [95%CI] = 1·42 [0·66,3·08]) masked this heterogeneity. Conclusion This hypothesis-generating finding suggests that parents may be more vulnerable to depression when their child is diagnosed with a life-shortening condition during the first few months of life. Mood in parents of infants diagnosed early needs to be monitored longitudinally and preventative strategies devised.