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Lipoproteinassociated phospholipase A₂(Lp-PLA₂) connects oxidised lipid metabolism to vascular inflammation, however evidence of its role in Middle Eastern populations' cardiovascular disease (CVD) is lacking. We analysed circulating LpPLA₂, inflammatory markers, and mRNA expression in a Saudi population. To compare Lp-PLA₂, markers TNF α and IL 6, oxidised LDL, LP-a, and lipid profile between CVD patients and healthy controls, assess mRNA upregulation, and analyse correlations between Lp-PLA₂ and markers.30 healthy people and 30 people with CVD who had been diagnosed with atherosclerosis were compared in an investigation. Fasting blood plasma was analyzed via ELISA to determine hematological, biochemical, and cardiovascular biomarkers. Using quantitative reverse transcription polymerase chain reaction (RT-qPCR), whole blood messenger RNA (mRNA) was analyzed for Lp-PLA₂, TNF α and IL 6. Compared with Healthy, CVD patients showed higher LpPLA₂ (419 ± 188 vs 101 ± 32 ng/mL; P<0.001), IL6 (74 ± 17 vs 40 ± 19 pg/mL; P<0.001), TNFα (4.4 ± 0.9 vs 3.7 ± 0.8 pg/mL; P<0.01), oxLDL (430 ± 143 vs 242 ± 67 pg/mL; P<0.001), and LP-a (134 ± 31 vs 90 ± 33 ng/mL; P<0.001), with a more atherogenic lipid profile (LDL 3.02 ± 0.63 vs 1.72 ± 0.63 mmol/L; P<0.001; HDL lower: P<0.01). mRNA expression of LpPLA₂, IL6, and TNFα was upregulated in CVD. LpPLA₂ correlated with IL6 (r=0.75, P<0.001), TNFα (r=0.36, P<0.01), oxLDL (r=0.85, P<0.001), and LDL (r=0.80, P<0.001). CVD is associated with concordant proteinlevel elevations and mRNA upregulation of LpPLA₂, IL6, and TNFα, supporting a feedforward inflammatory–oxidative axis. These data from a Saudi cohort extend international evidence and support targeting the LpPLA₂ cytokine oxidative pathway in atherosclerosis.