To examine the effect of high-dose interferon (IFN)-beta1a [44 microg administered subcutaneously (sc) 3 times weekly (tiw)] on tumor necrosis factor-alpha (TNF-alpha) and insulin-like growth factor-1 (IGF-1) levels in patients with relapsing-remitting multiple sclerosis (RRMS), and any correlation with clinical and magnetic resonance imaging (MRI) data. Previously treatment-naive patients with RRMS and an Expanded Disability Status Scale score < or = 3.5 were enrolled. At baseline, monthly for the first 5 months, and then after 12 months of treatment with 44 microg sc tiw of IFN-beta1a, all patients underwent clinical examination, assessment of serum TNF-alpha and IGF-1 levels and baseline, 5th, and 12th months to MRI scanning. Mean TNF-alpha values decreased significantly from months 0 to 12 of the study (P = 0.003), but mean IGF-1 values showed a nonsignificant reduction (P = 0.265). Serum levels of TNF-alpha and IGF-1 were sometimes correlated throughout the study, but no significant interactions were observed between serum TNF-alpha or IGF-1 and clinical or MRI findings. A borderline significant trend toward higher basal TNF-alpha levels was found in patients who developed new T1 lesions at 12 months compared with those who did not (P = 0.057). Interferon-beta1a therapy may reduce serum TNF-alpha levels in patients with RRMS, without a clear correlation with disease activity.