Objective To investigate the prevalence and severity of fatigue in adult patients with Pompe disease. Methods The Fatigue Severity Scale (FSS) was assessed in an international population of 225 adults with Pompe disease, a metabolic disorder presenting as a slowly progressive proximal myopathy. The FSS scores were compared to those of healthy controls and the relationship between the level of fatigue and other patient characteristics was investigated. Results The mean age of the participants was 47 (SD 13) years and the mean disease duration 11 (SD 8) years. 43% used a wheelchair and 46% had respiratory support, 29% needed both. 67% of the participants had a FSS score ≥5, indicating severe fatigue. The mean FSS score was 5.2 (SD 1.5), which was significantly higher than that of healthy controls (p < 0.001). Fatigue was not related to age, sex or disease duration. Patients who used a wheelchair or respiratory support were on average more fatigued than those who did not (p = 0.01). However, of the patients who did not use these aids, 59% also had a FSS score ≥5. FSS scores were highest among patients who reported a high frequency of sleep disorders, but patients who never experienced sleep difficulties were also fatigued (mean FSS score = 4.8). Conclusion Fatigue is highly prevalent among both mildly and severely affected adult patients with Pompe disease. The FSS appears a useful tool in assessing fatigue in Pompe disease.