Children with medical complexity (CMC) are vulnerable to respiratory illness hospitalization (RIH) and respiratory syncytial virus (RSV)-related hospitalization (RSVH) due to multisystem disorders and compromised airways. It is unknown whether RSV prophylaxis is effective, or if RSVH is associated with significant morbidities in CMC. The study objectives were to (1) determine the incidence of RSV-related infection in prophylaxed CMC during the first 3 years of life and (2) assess the burden of illness following RSVH. A single tertiary center, retrospective study, was conducted of CMC who received palivizumab during the 2012-2016 RSV seasons. Fifty-four subjects were enrolled; most received one (38.9%, n = 21) or two (57.4%, n = 31) seasons of prophylaxis (mean = 4.2 [SD = 1.24], palivizumab doses per season). The cohort comprised children with multiple medical conditions (n = 22, 40.8%), tracheostomy (n = 18, 33.3%), and invasive (n = 10, 18.5%) or non-invasive (n = 4, 7.4%) ventilation. Of the CMC, 24 were hospitalized 47 times for a viral-related respiratory illness. RSV incidence in the first 3 years of life was 7.4%. Viral-related RIH and RSVH rates were 44.4% (n = 24/54) and 1.9% (n = 1/54), respectively. Of the four RSV-positive children, one was ventilated for 9 days, two acquired nosocomial RSV that was managed on the ward, and one was discharged home under close complex care supervision. All four RSV-positive cases required additional oxygen during their illness. CMC experience a high viral-related RIH rate and palivizumab likely minimizes RSV-related events and associated morbidities. The efficacy of palivizumab in CMC, especially in those ≤ 3 years, should be prospectively evaluated.