Negative affect has been shown to be associated with high levels of pain and disability in osteoarthritis (OA) patients. As an explanation of this association, it was hypothesized that muscle weakness is a mediating factor between negative affect, pain and disability. Accordingly, negative affect enhances the patient's tendency to avoid pain-related activities; a low activity level induces muscle weakness, instability of joints and thus pain and disability. This theory leads to the prediction that the association between negative affect, pain and disability is most pronounced in patients with weak muscles. The prediction was tested in a study on patients with OA of the hip and/or knee. Regarding disability (but not pain), the prediction was confirmed. This study indicates that muscle weakness is a mediating factor between negative affect and disability in OA-patients.