Background Few studies focus on cross-cultural differences in Chronic fatigue syndrome (CFS). Purpose This study aimed to (1) compare fatigue severity and impairment, somatic complaints, psychological distress, and quality of life (QoL) in a population of Portuguese and Dutch patients; (2) explore the differential contribution of behavioral and cognitive determinants of fatigue severity; and (3) investigate the relation between fatigue severity and somatic complaints on one hand and QoL on the other in both populations. Method Eighty-five female patients from Portugal (Mean age0 47.54) and 167 female CFS patients from The Netherlands (Mean age044.93) participated in the study. All participants were surveyed for demographic and clinical characteristics, fatigue severity, somatic symptoms, psychological distress, (physical and psychological) QoL, physical activity, behavior regulation patterns, and illness representations. Results Cross-cultural differences were found in relation to working status, duration of fatigue symptoms, psychological distress, somatic complaints, and psychological QoL. Although behavioral characteristics and illness representations were significantly associated with fatigue severity in both Portuguese and Dutch patients, there were important differences in the determinants of CFS. Moreover, higher levels of fatigue and severity of other somatic complaints were related to poor QoL. Conclusions These findings show cross-cultural similarities and differences in clinical characteristics and psychological determinants of CFS that are important in view of diagnosis and treatment.