This report aims to describe the adverse respiratory events associated with the first pamidronate cycle in four infants with severe osteogenesis imperfecta (OI) who were less than 2 years of age. Fifty-nine infants with severe OI were commenced on cyclical intravenous pamidronate therapy in an observation trial. Routine observations were measured during each infusion cycle. During the first treatment cycle, four infants (7%) with preexisting respiratory compromise developed respiratory distress. The respiratory distress was successfully managed with bronchodilator therapy. Two of the infants required intensive care admission. There was no recurrence of respiratory distress with subsequent pamidronate infusion cycles. In infants with severe OI and preexisting respiratory compromise, the first pamidronate infusion cycle may be associated with an acute deterioration of respiratory function. The etiology is unclear but may involve cytokine release and/or hemodynamic compromise from fluid administration during the first infusion cycle. Close monitoring throughout the first treatment cycle is of paramount importance.