OBJECTIVES: To assess the effect of subcutaneous  Methylnaltrexone on generic Health Related Quality of Life using the EQ-5D index scores in patients on opioid therapy for chronic non-malignant pain with opioid-induced constipation. METHODS: In this study, 469 subjects were randomized to either methylnaltrexone daily (QD), every other day (QOD) dosing or placebo for 4 weeks. Eligibility criteria included an opioid dose of ≥50 mg oral morphine equivalents/day for ≥2 weeks and <3 rescue-free bowel movements (RFBMs)/week. Rescue laxative use was standardized and allowed if needed. Patients completed EQ-5D questionnaire on day 14 and day 28. EQ-5D index scores were compared between treatment and placebo groups using analysis of covariance, with treatment group as factor and baseline scores as covariate. RESULTS: Majority of the patients in the study were female (60%), Caucasian (90%), average age of 49 years and back pain (60%) was the most frequently reported pain condition. The mean daily baseline morphine equivalent opioid dose was 222 mgs. The mean ± SD baseline EQ-5D index scores were 0.45 ± 0.33 in QD, 0.47 ± 0.33 in QOD and 0.44 ± 0.35 in placebo groups respectively. The adjusted mean (± SE) change from baseline in index score on day 14 in QD (0.04 ± 0.02) and QOD groups (0.06 ± 0.02) were not statistically significant compared to placebo (0.02 ± 0.02). At the end of the double blind period (day 28), a significantly greater change from baseline in index scores was detected in the Methylnaltrexone QD dosing group (0.08 vs. –0.01; p<0.05) and QOD dosing group (0.08 Vs. -0.01; p<0.05) compared to placebo. CONCLUSIONS: Methylnaltrexone SC QD and QOD groups showed a significantly greater improvement in health related quality of life as measured by the EQ-5D index scores at the end of four weeks of therapy compared to placebo.