The diagnosis of cystic fibrosis (CF) can impact the mental health of caregivers. This study aimed to explore prevalence of postpartum depression (PPD) symptoms in caregivers of infants with CF or CFTR-related metabolic syndrome (CRMS). This prospective, observational study was conducted in a CF clinic at a tertiary hospital over 4 years. Caregivers of infants with CF/CRMS completed serial surveys over the first year of life. Surveys included the Edinburgh Postnatal Depression Scale (EPDS), Patient Health Questionnaire-9 (PHQ-9) and the General Anxiety Disorder-7 (GAD-7). A control group of healthy infant caregivers was used for comparative analysis of EPDS scores. Analyses were conducted on 55 caregivers of 42 infants with CF/CRMS and 915 caregivers of healthy infants. Caregivers of infants with CF/CRMS had a significantly higher prevalence of elevated EPDS scores and higher mean EPDS scores for visit 1 (age 1-2mo) and visit 3 (age 6-9mo) compared to healthy controls (p < 0.001 for both). There was a higher prevalence of caregivers identifying thoughts of self-harm in the CF/CRMS cohort (8.3%) compared to caregivers of healthy controls (1.2%) at visit 1 (p = 0.015) and at visit 3 (CF/CRMS 8.8%; control 1.7%; p = 0.030). EPDS scores correlated with PHQ-9 and GAD-7 scores, particularly earlier in the infant's life. Caregivers of infants with CF/CRMS may be at higher risk of PPD and thoughts of self-harm when compared to healthy controls. Given what is known about the impact of PPD on mental and physical health of children, early identification is vital for this population.