Human leukocyte antigen G (HLA-G) is a nonclassical HLA class I antigen that stands out for its immune regulatory properties. First recognized as a mediator of tolerance at the feto-maternal interface, HLA-G is considered a key molecule in protecting target tissue from autoaggressive inflammation.1 High serum levels of soluble HLA-G (sHLA-G) were found to predict graft acceptance in allotransplantation, whereas low levels seem to increase the risk of autoimmunity and account for higher disease activity in autoimmune diseases (e.g., rheumatoid arthritis).1 To evaluate its potential use as a biomarker in multiple sclerosis (MS), we analyzed sHLA-G serum protein in a large cohort of patients with clinically isolated syndrome (CIS) who developed MS during the 5-year observation period of the Betaferon/Betaseron in Newly Emerging Multiple Sclerosis for Initial Treatment (BENEFIT) trial.2 ### Methods. BENEFIT was a placebo-controlled phase III trial of interferon-β (IFNβ)–1b in patients with CIS.2 The study design and outcomes of BENEFIT have been reported elsewhere.2 All patients underwent Expanded Disability Status Scale (EDSS) assessment and brain MRI on a regular basis. The present study focused on patients who reached clinically definite MS (CDMS) during the trial (n = 209). From these patients, a total of 555 serum samples and 435 MRI scans were analyzed. Quantification of sHLA-G was performed using a commercially available ELISA kit (Exbio, Prague, Czech Republic). Nonparametric tests and Cox proportional hazards regression were used in the statistical analysis. A 2-sided p value < 0.05 was considered significant. ### Results. The analysis of “basal” sHLA-G serum levels in untreated patients yielded a highly heterogeneous result (figure 1A). While sHLA-G was undetectable in 22.1% of patients, 12.7% had excessive amounts of sHLA-G serum …