We developed the SupportPrim PT clinical decision support system (CDSS) using the artificial intelligence method case-based reasoning to support personalised musculoskeletal pain management. The aim of this study was to evaluate the effectiveness of the CDSS for patients in physiotherapy practice. A cluster randomised controlled trial was conducted in primary care in Norway. We randomised 44 physiotherapists to (1) use the CDSS alongside usual care or (2) usual care alone. The CDSS provided personalised treatment recommendations based on a case base of 105 patients with positive outcomes. During the trial, the case-based reasoning system did not have an active learning capability; therefore, the case base size remained the same throughout the study. We included 724 patients presenting with neck, shoulder, back, hip, knee, or complex pain (CDSS; n = 358, usual care; n = 366). Primary outcomes were assessed with multilevel logistic regression using self-reported Global Perceived Effect (GPE) and Patient-Specific Functional Scale (PSFS). At 12 weeks, 165/298 (55.4%) patients in the intervention group and 176/321 (54.8%) in the control group reported improvement in GPE (odds ratio, 1.18; confidence interval, 0.50-2.78). For PSFS, 173/290 (59.7%) patients in the intervention group and 218/310 (70.3%) in the control group reported clinically important improvement in function (odds ratio, 0.41; confidence interval, 0.20-0.85). No significant between-group differences were found for GPE. For PSFS, there was a significant difference favouring the control group, but this was less than the prespecified difference of 15%. We identified several study limitations and recommend further investigation into artificial intelligence applications for managing musculoskeletal pain.