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Objective: This explorative study investigates the moderating effect of sex and baseline pain characteristics on the effectiveness of preoperative pain neuroscience education (PNE) plus knee joint mobilization versus biomedical education plus knee joint mobilization in patients who have knee osteoarthritis and are scheduled to undergo total knee arthroplasty (TKA). Methods: After baseline assessment of self-reported questionnaires (pain intensity, disability, symptoms of central sensitization and pain cognitions) and quantitative sensory testing, 44 participants with knee osteoarthritis were randomized into the PNE plus knee joint mobilization or biomedical education plus knee joint mobilization group. The questionnaires were retaken directly after and 1 month after 4 sessions of treatment and at 3 months after surgery. Based on baseline quantitative sensory testing results, the sample was subdivided into a high (showing high experimental pain levels and low pressure pain thresholds) and low pain cluster using principal components analysis and cluster analysis. Therapy effects over time were evaluated using 3-way analysis of variance, with time as the within factor and treatment, sex, and baseline pain cluster as between factors. Results: Women benefited significantly more from the PNE intervention compared with the control intervention in terms of self-reported symptoms of central sensitization. For both pain clusters, differences in therapeutic effects concerning pain intensity and pain cognitions were found, with higher superiority of the PNE intervention in the high-pain cluster subgroup compared with the low-pain cluster. Conclusion: Based on these explorative analyses, it can be concluded that sex and preoperative pain measures may influence the effectiveness of preoperative PNE for some specific outcome measures in people scheduled to undergo TKA. Impact: Although further research on this topic is needed, the potential influence of sex and preoperative pain measures on the effectiveness of preoperative PNE should be considered when implementing this intervention in people undergoing TKA. [ABSTRACT FROM AUTHOR]