Objectives: Caregivers of infants with cystic fibrosis (CF) carry a heavy treatment burden for their child along with the inherent difficulties of raising an infant. This study investigated the impact of self-reported caregiver mental health diagnoses and social barriers during the 1st year of life on clinical outcomes. Methods: A retrospective chart review was conducted for infants seen in a large tertiary hospital CF clinic over a 5-year period. Baseline characteristics were collected, and documentation from physician and social work notes were reviewed. Demographics and clinical characteristics were compared by the presence or absence of self-reported mental health diagnoses, social barriers, and "emotional concern." Results: Analyses were conducted on 71 patients. Thirty-five percent of caregivers disclosed mental health diagnoses, 52% identified social barriers to care, and 55% reported feeling upset or fatigued. Having a caregiver with a self-reported mental health diagnosis was associated with tobacco smoke exposure (p < .001) and increased odds of hospitalizations (odds ratio [OR], 3.01; 95% confidence interval [CI], 1.49-6.06), emergency department/urgent care visits (OR, 3.17; 95% CI, 1.32-7.64), and longer lengths of stay (OR, 1.93; 95% CI, 1.69-2.20). Caregivers who expressed emotional concern had infants with significantly lower weight-for-length percentiles (p = .012). Discussion: Caregiver mental health and social barriers to care are important determinants to address as they may impact clinical outcomes in infants with CF. Identifying barriers and struggles early increases the likelihood that clinical teams can intervene and provide support. Further research into mental health and socioeconomic barriers faced by caregivers of infants with CF is crucial.