Objective Predictors of arthritis development in patients with anti-citrullinated protein antibodies (ACPAs) and musculoskeletal symptoms are needed for risk stratification and to improve clinical outcomes. The aim of this study was to assess the relationship between serum protein electrophoresis (SPE) constituents and the development of clinical arthritis in ACPA-positive patients with musculoskeletal pain. Method We prospectively followed 82 ACPA-positive patients with musculoskeletal pain but no baseline arthritis during a median of 72 months (interquartile range 57–81 months). The primary outcome was arthritis development, as judged by clinical examination. SPE constituents were evaluated in baseline sera by immunoturbidimetric methods. Serum levels of the analysed proteins (albumin, orosomucoid, α1-anti-trypsin, haptoglobin, and immunoglobulins IgA, IgG, and IgM) were related to arthritis development by Cox regression analyses. Results During the follow-up period, 39/82 patients (48%) progressed to arthritis. Median baseline levels of orosomucoid and α1-anti-trypsin were higher in patients who developed arthritis than in those who did not (p = 0.04), while median albumin levels were significantly lower (p = 0.03). Immunoglobulin levels did not differ between the groups. Univariable analysis demonstrated a significantly increased risk of arthritis with elevated baseline haptoglobin [hazard ratio (HR) 2.53, 95% confidence interval (CI) 1.32–4.85, p = 0.005] and orosomucoid levels (HR 2.63, 95% CI 1.09–6.31, p = 0.03). However, neither remained significant in multivariable analysis adjusting for elevated C-reactive protein (CRP) levels. Conclusion SPE does not add prognostic value for arthritis development in ACPA-positive patients with musculoskeletal pain.