Airway secretions and infections are common in cerebral palsy and neuromuscular diseases. Chest physiotherapy is standard therapy but effort is substantial. High-frequency chest wall oscillation is used in cystic fibrosis but tolerability and safety data in cerebral palsy and neuromuscular disease are limited. A prospective, randomized, controlled trial of high-frequency chest wall oscillation and standard chest physiotherapy was performed in participants with neuromuscular disease or cerebral palsy. Outcome measures included respiratory-related hospitalizations, antibiotic therapy, chest radiographs, and polysomnography. Care-givers were questioned regarding therapy adherence. A total of 28 participants enrolled, 23 completed (12 chest physiotherapy, mean study period 5 months). No adverse outcomes were reported. Adherence to prescribed regimen was higher with high-frequency chest wall oscillation (P = .036). Our data suggest safety, tolerability, and better compliance with high-frequency chest wall oscillation. Improvement in airway clearance may help prevent hospitalizations. Larger controlled trials are required to confirm these results.