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OBJECTIVE: The literature on psychosocial job factors and musculoskeletal pain is inconclusive in part due to insufficient control for confounding by biomechanical factors. The aim of this study was to investigate prospectively the independent effects of effort–reward imbalance (ERI) at work on regional musculoskeletal pain of the neck and upper extremities of call center operators after controlling for (i) duration of computer use both at work and at home, (ii) ergonomic workstation design, (iii) physical activities during leisure time, and (iv) other individual worker characteristics. METHODS: This was a one-year prospective study among 165 call center operators who participated in a randomized ergonomic intervention trial that has been described previously. Over an approximate four-week period, we measured ERI and 28 potential confounders via a questionnaire at baseline. Regional upper-body pain and computer use was measured by weekly surveys for up to 12 months following the implementation of ergonomic interventions. Regional pain change scores were calculated as the difference between average weekly pain scores pre- and post intervention. RESULTS: A significant relationship was found between high average ERI ratios and one-year increases in right upper-extremity pain after adjustment for pre-intervention regional mean pain score, current and past physical workload, ergonomic workstation design, and anthropometric, sociodemographic, and behavioral risk factors. No significant associations were found with change in neck–shoulder or left upper-extremity pain. CONCLUSIONS: This study suggests that ERI predicts regional upper-extremity pain in ­computer operators working ≥20 hours per week. Control for physical workload and ergonomic workstation design was essential for identifying ERI as a risk factor.