OBJECTIVES: Estimate the cost-effectiveness of Pregabalin (PGB) versus Usual Care (UC) in refractory out-patients with Neuropathic Pain (NeP) treated according to usual medical practice in Primary Care settings (PCS) in Spain. METHODS: Data extracted from a 12-week non-interventional prospective study conducted to ascertain the cost of NeP were used. PGB naïve patients treated with UC or PGB, matched by age (+5years), sex and pain intensity (+5pts), refractory (≥40VAS-McGill) to previous treatment during the prior 6 months, were selected in a 1:1 ratio. Patients could switch to PGB (monotherapy/add-on) or to UC (non-narcotics, opiates, antidepressants and/or anticonvulsants). Time horizon was 12 weeks. Effectiveness was quality-adjusted life years (QALY) gain. Perspectives of the National Health Service (NHS) and society (2006) were included, and expressed as an incremental cost effectiveness ratio (ICER). Bootstrapping techniques (10,000 re-samples) were used to obtain the probabilistic ICER, its 95% percentile confidence interval (CI) and the cost-effectiveness acceptability curve. RESULTS: A total of 160 patient-pairs were extracted. Compared with UC, PGB was associated with significantly higher QALY gain; 0.0374 ± 0.0367 vs. 0.0224 ± 0.0313 (p<0.001). Notably, although drug costs were higher for PGB (€251±125 vs. €104±121, p<0.001), its QALY gain did not incur a higher overall total cost (€1335±1302 vs. €1387±1489; p=0.587), nor higher health care costs (€529±438 vs. €560±672; p=0.628). In fact, the ICER was dominant for total and health care costs, with CIs respectively, dominant-€17,268, and dominant-€6,508. ICER for drug costs was €10,672/QALY (dominant-€19,858). The 99% of the re-samples were below the threshold of €30,000/QALY. CONCLUSIONS: Versus usual care in the community medical setting, pregabalin is highly cost-effective in the treatment of refractory NeP patients. The high indirect costs and increased health care costs associated with the treatment of refractory patients, which offset higher cost of pregabalin, highlight the economic burden of the condition on society.