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Background: The onset of chronic fatigue syndrome (CFS) has been shown to be associated with several immunological conditions such as infections or atopy. The aim of this study was to clarify the risk of chronic fatigue syndrome following the diagnosis of psoriasis, an immune-related dermatological disease, by analyzing the National Health Insurance Research Database of Taiwan. Method: 2616 patients aged 20 years or older with newly diagnosed psoriasis during 2004–2008 and 10,464 participants without psoriasis were identified. Both groups were followed up until the diagnoses of CFS were made at the end of 2011. Results: The relationship between psoriasis and the subsequent risk of CFS was estimated through Cox proportional hazards regression analysis, with the incidence density rates being 2.27 and 3.58 per 1000 person-years among the non-psoriasis and psoriasis populations, respectively (adjusted hazard ratio [HR] = 1.48, with 95% confidence interval [CI] 1.07–2.06). In the stratified analysis, the psoriasis group were consistently associated with a higher risk of CFS in male sex (HR = 2.05, 95% CI 1.31–3.20) and age group of ≥ 60 years old (HR = 2.32, 95% CI 1.33–4.06). In addition, we discovered that the significantly increased risk of CFS among psoriasis patients is attenuated after they receive phototherapy and/or immunomodulatory drugs. Conclusions: The data from this population-based retrospective cohort study revealed that psoriasis is associated with an elevated risk of subsequent CFS, which is differentiated by sex and age. [ABSTRACT FROM AUTHOR]