Health-related, quality of life (HRQoL) is an important outcome in clinical trials of patients with Charcot-Marie-Tooth disease (CMT). In a cross-sectional survey of 295 Australian adults with CMT, HRQoL was measured using the Short Form-36 (SF-36) and predictors of reduced HRQoL were identified with a CMT-specific health status questionnaire. People with CMT demonstrated lower HRQoL scores than the general Australian population in all SF-36 dimensions. The disparity between people with CMT and normative data was greater for physical dimensions than for mental health dimensions. SF-36 scores were generally lower in older vs younger people, but not between men and women, or between CMT types. HRQoL in CMT was predicted strongly by lower limb weakness and to a lesser extent by leg cramps, suggesting clinical trials targeting weakness and cramps may improve HRQoL in patients with CMT.