OBJECTIVES: Narcolepsy is a disease resulting in excessive day-time sleepiness (EDS) and cataplexy (an abrupt temporary loss of voluntary muscular tone, sometimes evoked by an emotional stimulus). Narcolepsy affects more than 20,000 people in the UK and has many implications for health-related quality of life (HRQL). The objective of our systematic review was to identify and assess the suitability of instruments used to measure the impact of narcolepsy on HRQL. METHODS: A systematic search of Scopus (1966-2008) was conducted using terms synonymous with “narcolepsy” combined with terms associated with measuring “QoL”. Once the measures were identified, further searches were undertaken to explore their use, development history and demonstrated measurement properties. RESULTS: A total of 141 abstracts were screened yielding 18 studies that used patient-reported outcome (PRO) measures. In total, 13 PROs were used to evaluate symptoms, sleep disorders, anxiety/depression, and HRQL, most of which can be more accurately described as health status (SF-36, EQ-5D) or satisfaction (QLI) measures. Only two PROs were narcolepsy-specific; the Ullanlinna Narcolepsy Scale (UNS) and Stanford Narcolepsy Questionnaire, both measuring symptoms. No narcolepsy-specific HRQL questionnaires have been used to date. Generic measures such as the SF-36, QLI and the EQ-5D can be useful when making comparisons with other medical conditions but have limited value for assessing the full impact of narcolepsy because they include irrelevant items and exclude relevant issues. Furthermore, the generic measures do not demonstrate measurement properties relevant to this specific population nor do they demonstrate adequate development histories as required by regulatory bodies. CONCLUSIONS: There is an absence of instruments measuring narcolepsy-specific HRQL. Existing generic measures are likely to underestimate the full impact of narcolepsy on HRQL and therefore underestimate the full potential benefits of new treatments. A new questionnaire, which adheres to current regulatory guidelines, is therefore needed to assess the full impact of narcolepsy on HRQL.