Objective: Cutaneous lymphomas may have a profound impact on patients' health-related quality of life (HRQoL) and psychological well-being. A detailed investigation of HRQoL, analyzing its correlation with clinical variables and biological parameters, has not been done before. Methods: The study population consisted of patients with cutaneous T- cell (CTCL) or B-cell lymphoma (CBCL), consecutively recruited in the outpatient and the inpatient clinics of an Italian hospital. Data was collected using a dermatology-specific questionnaire, the Skindex-29 (symptoms, emotions, and functioning scales), and an oncology-specific questionnaire, the EORTC QLQ-C30 (15 scales, concerning physical and emotional aspects). Results: Of 95 patients, there were 24 patients with CBCL, 59 with mycosis fungoides (MF), and 12 with Sézary syndrome (SS). The most frequent problems appearing from the EORTC QLQ-C30 analysis were fatigue, pain, and insomnia. The differences among hystotypes were particularly high in the global health status and emotional functioning scales, with a worse HRQoL in patients with SS, followed by MF, and CBCL. HRQoL impairment in all hystotypes was higher in women than in men, in patients with probable anxiety or depression, and when the disease worsened. The multivariate analysis of the independent role of each variable confirmed these results. The highest prevalence of probable anxiety or depression was observed in patients treated with systemic steroids (60%) and interferon (50%). Conclusion: The detailed evaluation of HRQoL and psychological problems in patients with cutaneous lymphomas, and their relationship with clinical variables, may give important information on the course of the disease as well as the possible effect of treatment.