Background In the past decade, a few studies have suggested that psoriasis could be associated with the presence of mild cognitive deficits. Objectives The aim of the present matched case-control study was to investigate several cognitive domains (executive functions, verbal memory, attention, and language) in a sample of outpatients with psoriasis. We also investigated whether cognitive impairment was associated with poor health-related quality of life (HRQoL) in patients with psoriasis. Methods Fifty adult outpatients and 50 age- and sex-matched healthy controls were administered a battery of neuropsychological tests investigating major cognitive domains, psychopathology (anxiety and depression), alexithymia, and HRQoL. Results At the bivariate level, psoriasis patients (compared to healthy controls) performed worse on most of the neuropsychological tests, and they also reported more anxiety and depressive symptoms, higher scores for alexithymia, and worse physical and mental health. At the multivariate level, cognitive performance was independently associated with psoriasis even when controlling for psychopathology and alexithymia. Conclusions Patients with psoriasis show impaired cognitive performance, high levels of anxiety and depression, and impaired quality of life. Based on the current results, clinicians should assess the presence of psychological symptoms in their patients and evaluate whether the presence of cognitive deficits is limiting the patients' ability to cope with the disease.