There is controversy whether determination of antibodies against myelin, myelin oligodendrocyte glycoprotein, and myelin basic protein in serum from patients with a first episode suggestive of multiple sclerosis is of prognostic value. We evaluated whether detection of anti-myelin antibodies in serum indicate a worse course with earlier time to a second relapse and increased progression of disability. We conducted a prospective study at the Department of Neurology, Inselspital Bern, Switzerland from 2004-2008 in patients presenting with a clinically isolated syndrome (CIS) and a follow-up of at least four months. Anti-myelin antibodies were assessed by Western blot. Results were correlated with clinical course and sex. Among 93 consecutive patients with a CIS, 74 (80%) were positive for either one or both anti-myelin antibodies. A relapse occurred in 49 (53%) and the median EDSS was 2 (range 1-3.5) after a mean observation period of 20 months. Presence of anti-myelin antibodies at CIS neither increased the risk for a second relapse nor for progression of disability. Stratification for gender did not reveal differences for any of the clinical surrogates. The sole determination of anti-myelin antibodies in serum is of limited prognostic value for the identification of patients with different short-term course.