Chronic progressive external ophthalmoplegia (CPEO) is a relatively common mitochondrial disorder. Weakness of the extra-ocular, limb girdle and laryngeal muscles are established clinical features. Respiratory muscle involvement however has never been studied systematically, even though respiratory complications are one of the main causes of death. We therefore determined the prevalence and nature of respiratory muscle involvement in 23 patients with genetically confirmed CPEO. The main finding was decreased respiratory muscle strength, both expiratory (76.8% of predicted, p = 0.002) and inspiratory (79.5% of predicted, p = 0.004). Although the inspiratory vital capacity (92.5% of predicted, p = 0.021) and the forced expiratory volume in 1 s (89.3% of predicted, p = 0.002) were below predicted values, both were still within the normal range in the majority of patients. Expiratory weakness was associated with a decreased vital capacity (ρ = 0.502, p = 0.015) and decreased peak expiratory flow (ρ = 0.422, p = 0.045). Moreover, expiratory muscle strength was lower in patients with limb girdle weakness (62.6 ± 26.1% of predicted vs. 98.9 ± 22.5% in patients with normal limb girdle strength, p = 0.003), but was not associated with other clinical features, subjective respiratory complaints, disease severity or disease duration. Since respiratory involvement in CPEO is associated with severe morbidity and mortality, the present data justify periodic assessment of respiratory functions in all CPEO patients.