Chronic pain has a significant impact on quality of life. Measurement of health-related quality of life (HRQoL) is essential in the assessment of pain management outcomes, but different instruments have produced varying results. We assessed the validity of 2 HRQoL instruments, EuroQol 5 dimensions questionnaire (EQ-5D) and 15-dimensional health-related quality of life measure (15D), in patients with challenging chronic pain. Three hundred ninety-one chronic noncancer pain patients referred to tertiary pain clinics completed EQ-5D, 15D, and a broad set of questionnaires mapping socioeconomic factors, self-rated health, pain intensity and interference, depression, pain acceptance, pain-related anxiety, and sleep. The 2 HRQoL instruments were compared with each other, and head-to-head comparisons were made with self-rated health and the symptom-specific questionnaires. 15D and EQ-5D showed moderate agreement (ρ = 0.66), but there were also considerable differences between the instruments. 15D correlated better with self-rated health than EQ-5D (ρ = −0.62 vs −0.45, P < 0.001). The EQ-5D appeared less sensitive than 15D especially in those patients with chronic pain who had a better health status. The principal component constructed from measures of pain intensity and interference, anxiety, pain acceptance, depression, and sleep had higher standardized beta coefficients with 15D than with EQ-5D (P = 0.038). The principal component explained more variance in the 15D (R2 = 0.65) than in the EQ-5D (R2 = 0.43). The study identified differences in the pain-related variables between the EQ-5D and the 15D. In patients with chronic pain, both instruments are valid, but 15D appears somewhat more sensitive than EQ-5D.