The aim of this 1 week study was to compare the biologic effects induced by Betaseron and AVONEX using their approved dose, route, and schedule. Sixteen healthy volunteers were randomly assigned to receive either a single i.m. dose of AVONEX (6 million International Units [MIU]) or, every other day s.c. doses of Betaseron (8 MIU). Common side effects associated with interferon-beta (IFN-beta) treatment and biologic response parameters (neopterin, beta2-microglobulin, interleukin-10 [IL-10], and MxA protein levels in blood) were measured. Ibuprofen was administered to all subjects throughout the study. Fever, chills, and myalgia occurred most frequently and with the greatest severity between 6 and 12 h after the first dose of either IFN-beta. Despite the additional dosing of subjects in the Betaseron group, the incidence, duration, and severity of the side effects were not significantly different from those in the AVONEX group. Biologic response parameters reached similar maximum concentrations in both treatment groups. In the Betaseron group, neopterin and beta2-microglobulin levels remained significantly greater than baseline throughout the 7 day study, whereas those in the AVONEX group were elevated only through day 5. Betaseron treatment significantly increased IL-10 levels above baseline, but AVONEX treatment did not. The overall induction of neopterin, beta2-microglobulin, and IL-10 (as measured by area under the concentration-time curve) was significantly greater in the Betaseron group than the AVONEX group (p = 0.031). The results of this study demonstrate that the approved Betaseron dosing regimen, in combination with ibuprofen use, provided a significantly greater and more consistently elevated biologic response compared with that of AVONEX and did so with a side effects profile comparable to that of once a week AVONEX dosing.