Background: Musculoskeletal (MS) complaints are reported commonly, but the extent to which such complaints reflect the severity of site-specific pathology or a more generalized susceptibility to feel pain/discomfort is uncertain. Both site-specific and more widespread MS conditions have been shown to be linked to anxiety and depression, but the nature of this relationship is poorly understood. In the present study the role of neuroticism as a shared risk factor that may possibly explain the co-occurrence between anxiety–depression and MS complaints was investigated. Method: The sample consisted of 746 monozygotic and 770 dizygotic twins in the age group of 50–65 years (M = 57.11, SD = 4.5). Using Cholesky modeling, genetic and environmental influences on neuroticism, anxiety–depression and MS symptoms, and the associations among these phenotypes were determined. Results: A single factor accounted for about 50% of the overall variance in MS symptom reporting. The best-fitting biometric model included sex-specific additive genetic and individual-specific environmental effects. All 3 phenotypes were strongly influenced by genetic factors, heritability (h2) = 0.41–0.56. Furthermore, while there was a considerable overlap in genetic risk factors among the 3 phenotypes, a substantial proportion of the genetic risk shared between MS complaints and anxiety–depression was independent of neuroticism. Conclusion: Evidence for a common underlying susceptibility to report MS symptoms, genetically linked to both neuroticism and anxiety–depression symptoms, was found.