No studies have assessed which variables determine deterioration of Quality of Life (QoL) and disability in Charcot-Marie-Tooth disease (CMT). The aim of our study was to assess which are the variables that influence QoL and disability in patients with CMT. We performed a large prospective multicenter (six centers see affiliations) multidimensional study by using validated clinical, disability, and quality of life measurements. Multivariate analysis was performed using QoL as dependent variables and duration of symptoms, age, gender and CMT type, depression and disability measurements as independent variables. Two hundred eleven patients were enrolled (60% women, mean age 42.5 years). QoL was highly significantly deteriorated with respect to the Italian normative sample. The physical aspect of QoL was mainly related to disability (but it does not increase with age probably for an adaptation between expectation and reality). The mental QoL is influenced by depression (hence we have to consider this aspect approaching CMT patients). Moreover we observed that women refer more severe symptoms than men and that some CMT subtypes are related to higher and others to lower bodily pain. Multiperspective assessment of CMT showed new aspects of CMT we have to deal with: differences between men and women, presence of pain and depression.