OBJECTIVES: Patients with failed back surgery syndrome (FBSS) and chronic neuropathic pain experience levels of health-related quality of life (HRQoL) that are considerably lower than those reported in other areas of chronic pain. Interventions aimed at reducing pain in FBSS patients are expected to bring considerable HRQoL improvements. Using data from the multinational PROCESS trial, we investigated the longitudinal relationship between generic HRQoL - assessed using two instruments often used in clinical trials (i.e. the SF36 and EuroQol5D) - and disease specific outcome measures (i.e. Oswestry Disability Index [ODI], leg and back pain visual analogue scale [VAS]) in neuropathic patients with FBSS. METHODS Multivariate hierarchical regression models to capture the longitudinal trend in the dependent variables (i.e. generic HRQoL), and to assess their relationship with patient baseline variables and clinical history. RESULTS Generic HRQoL was univariately consistently associated with disease specific outcome measures: ODI (correlation coefficient: -0.462 to -0.638) and leg pain VAS (correlation coefficient: -0.165 to -0.436). In multilevel regression analysis, baseline HRQoL and ODI were found to be significant predictors of generic HRQoL (all p<0.001). Leg pain was predictive of EuroQol5D and the SF36 physical component summary score (both p<0.001) but not of its mental component summary score (p=0.201). Baseline socio demographic characteristics (age and gender), clinical history (time since last back surgery and number of back surgeries), location of pain and intensity of back pain were not predictive of generic HRQoL (all p>0.10). CONCLUSIONS Reduction in leg pain and functional disability is statistically significantly associated with improvements in generic HRQoL. This is the first study to investigate the longitudinal relationship between generic and disease specific HRQoL of neuropathic pain patients with FBSS, using multinational data.