A member of the A2 phospholipase superfamily, the enzyme lipoprotein-associated phospholipase A2 (Lp-PLA2), is involved in atherogenic processes. Lp-PLA2 mass and activity were measured by the enzyme-linked immunosorbent assay and by a colorimetric method, respectively, and compared among 63 multiple sclerosis (MS) patients and 47 age-matched healthy controls (HCs). Lp-PLA2 plasma levels were significantly higher in MS patients (236.7 ± 10 ng/ml) compared to HCs (197.0 ± 7 ng/ml) (p = 0.003), but LP-PLA2 activity did not differ between the two groups. Both Lp-PLA2 plasma mass and activity were higher in secondary progressive (mass 247.0 ±15.5 ng/ml, p = 0.05; activity 156.1 ±6 nmol/min/ml, p = 0.003) compared to relapsing-remitting MS patients (mass 227.0 ± 16 ng/ml; activity 128.8 ± 5 nmol/min/ml) and compared to HCs. Lp-PLA2 plasma activity was associated with measures of MS clinical disability. However, this association was attenuated after adjustment for the components of lipid profiles.