ABSTRACT Background Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglia surface receptor that aids in tissue repair and debris clearance. The soluble form, sTREM2, found in both blood and cerebrospinal fluid, is considered a biomarker for microglial activation. Based on the central role of microglia in MS pathogenesis, we aimed to investigate whether serum sTREM2 levels could predict disability progression in patients with primary progressive MS. Methods Serum levels of sTREM2 were measured at baseline using a single‐molecule array assay in a multicenter cohort of 137 primary progressive multiple sclerosis (PPMS) patients. Univariable and multivariable linear models evaluated the association between sTREM2 levels and EDSS change at 2 years, 6 years, and last follow‐up. Results While an association was observed at 2 years only in non‐inflammatory PPMS patients, no consistent relationship was found between sTREM2 levels and disability progression over longer follow‐up. Conclusions These findings suggest that serum sTREM2 may have limited value as a biomarker of disability progression in PPMS.