Serotonin (5-HT) is involved in pain modulation via descending pathways in the central nervous system. The aim of this study was to test if escitalopram, a selective serotonin reuptake inhibitor (SSRI), would relieve pain in polyneuropathy. The study design was a randomized, double-blind, placebo-controlled cross-over trial. The daily dose of escitalopram was 20mg once daily. During the two treatment periods of 5 weeks duration, patients rated pain relief (primary outcome variable) on a 6-point ordered nominal scale. Secondary outcome measures comprised total pain and different pain symptoms (touch- or pressure-evoked pain, lancinating pain, constant burning or deep aching pain) by the use of 0-10-point numeric rating scales. Changes in health-related quality of life and severity of depression were measured with the SF-36 and the Major Depression Inventory (MDI). Forty-one patients were included in the data analysis. Patients reported a better pain relief during treatment with escitalopram compared with placebo (p=0.001). Total pain and different pain symptoms were lower during escitalopram treatment (p=0.001-0.024). The Number needed to treat (NNT) to obtain one patient with good or complete pain relief was 6.8. Health-related quality of life and depressive symptoms were unaltered (p=0.086-1.0). Five patients (10.4%) discontinued the study because of adverse effects during escitalopram. This study found a pain-relieving effect of escitalopram in patients with painful polyneuropathy, but a clinically relevant effect was obtained in only few patients. Currently, the drug cannot be recommended as a standard treatment in neuropathic pain.