The aim of this study was to determine circulating omega-6, omega-3 polyunsaturated fatty acids and prostaglandin E2 (PGE2) levels in steady state sickle cell disease (SCD) patients. Blood was collected from healthy hemoglobin volunteers and steady state homozygous HbSS patients who had not received blood transfusions in the last 3 months. Plasma levels of arachidonic acid (AA, C20:4n-6), dihomo-gamma-linolenic acid (DGLA, C20:3n-6), eicosapentaenoic acid (EPA, C20:5n-3) and docosahexaenoic acid (DHA, C22:6n-3) were determined by an optimized multiple reaction monitoring method using ultrafast liquid chromatography coupled with tandem mass spectrometry. PGE2 was measured in serum samples by enzyme immunoassay. Plasma AA and DGLA were significantly increased while EPA and DHA were significantly decreased in SCD plasma compared to control. Serum PGE2 levels, AA/DHA and AA/EPA ratio was significantly higher in SCD patients when compared to control group. The significant increase in PGE2 levels, AA/EPA and AA/DHA ratio confirms the presence of a proinflammatory state in SCD patients.