Objective: To study whether tumor necrosis factor (TNF) α or interferon (IFN) γ production by stimulated white blood cells precedes or accompanies clinical and magnetic resonance imaging signs of disease activity in patients with multiple sclerosis. Design: Prospective study with a follow-up of 9 months. Setting: Patients visiting an outpatient university clinic. Patients: The 30 Amsterdam-based patients (28 completing all evaluations) participating in a multicenter, randomized, placebo-controlled, double-blind trial of a chimeric anti-CD4 antibody in the treatment of active relapsing-remitting and secondary progressive multiple sclerosis. Patients in both treatment arms were included, because for these patients anti-CD4 treatment in this study did not affect TNF-α and IFN-γ production and did not reduce signs of disease activity on magnetic resonance imaging. Main Outcome Measure: Distribution of classes of TNF-α and IFN-γ production (expressed as z scores) in patients with or without clinical or magnetic resonance imaging signs of disease activity. Results: One month preceding exacerbations of multiple sclerosis, there was a shift toward higher z scores of TNF-α production (P<05), but not of IFN-γ production. There was no statistically significant relationship between IFN-γ and TNF-α production and magnetic resonance imaging markers of multiple sclerosis activity. Conclusion: The production of TNF-α, and not of IFN-γ, is significantly higher in patients with multiple sclerosis before exacerbations than in patients with stable disease. Although present, this relationship is too weak to use TNF-cα production as a surrogate marker of disease activity in multiple sclerosis.