To investigate quality of life in an international population of patients with late-onset Pompe disease. Data on quality of life (SF-36), age, sex, disease duration, wheelchair use, and use of artificial ventilation were collected for 210 adults with Pompe disease from Australia, Germany, the Netherlands, the United Kingdom, and the United States. SF-36 scores were compared between countries and related to patient characteristics. In addition, for the Dutch subgroup (n = 51), comparisons with the general population and 1-year follow-up assessments were performed. No significant differences between countries were found for the four physical health scales. Mean scores on the vitality, role functioning-emotional, and mental health scale differed between countries, but these differences were not consistent. Wheelchair use was associated with lower physical and social functioning scores (B = -23.6 and -15.1, p < 0.001), and the use of artificial ventilation with lower physical functioning scores (B = -8.4, p = 0.004). Patients reported significantly poorer quality of life than the general population on the physical functioning, role functioning-physical, general health, vitality, and social functioning scales. No significant differences in SF-36 scores were found between the baseline and 1-year follow-up measurement. Patients with late-onset Pompe disease are, on average, markedly affected on the physical health domains of quality of life, but score only slightly lower than the general population on the mental health domains.