Inhaled hypertonic saline (HS) positively affects both lung function and pulmonary exacerbations in children and adults with cystic fibrosis (CF). Early initiation of treatment may potentially reduce lung function decline and improve outcome of CF patients. However, the safety and tolerability of HS have not been established in infants and young children. We conducted a prospective trial of inhaled HS in infants with CF. Raised volume rapid thoracoabdominal compression (RVRTC) maneuvers were performed at baseline, 10 min after salbutamol inhalation and 15 min after inhalation of a 7% HS solution. Oxygen saturation, respiratory rate, heart rate, and cough frequency were recorded during each inhalation. A clinically important change in lung function was defined a priori as a change in FEV 0.5 of ≥20%. Thirteen infants (5 female) aged 25–140 weeks were enrolled in the study. Overall, there was no difference between FEV0.5 or FEF25–75 at baseline, after bronchodilator or after HS. Respiratory and heart rate as well as oxygen saturation remained stable during inhalation of the HS. Three infants had cough during inhalation; one of the infants woke up due to cough but recovered within 5 min. No other side effects were observed during or immediately after inhalation. There was no difference in microbiologic yield between pre‐ and post‐HS throat swabs. In this pilot study, inhalation of HS was well tolerated in CF infants. These results support a study of the efficacy of HS in this age group. Pediatr Pulmonol. 2007; 42:471–476. © 2007 Wiley‐Liss, Inc.