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Background: Heat shock protein 27 (HSP27) is found in several cell types of adults, such as cardiomyocytes, and endothelial cells. It is expressed in response to different cellular stress conditions. HSP27 decreases the levels of reactive oxygen species (ROS) and dyslipidemia is closely associated with increased endothelial production of reactive oxygen species (ROS). Objective: Higher serum HSP27 antigen and anti-HSP27 antibodies have been reported in patients with unstable angina and myocardial infarction Methods: This population-based case-control study was conducted in 2018. We investigated serum anti-HSP27 antibody titers in all participants with dyslipidemia from the Mashhad stroke and heart atherosclerotic disorder (MASHAD) study (n=8141) and those who were healthy in terms of dyslipidemia (n=1637) using an in-house enzyme-linked immune sorbent assay (ELISA) in individuals with dyslipidemia. Findings: Anti-HSP27 titers were significantly lower in individuals with dyslipidemia compared to people without dyslipidemia (P=0.036). Conclusion: Our results revealed that the anti-HSP27 antibody titer was lower in the participants with dyslipidemia than in the negative group. However, there may be a confounding effect of drug therapy. In a subgroup of dyslipidemic subjects, we observed lower anti-HSP27 antibody titers in patients treated with some drugs (statins or corticosteroids, non-steroidal anti-inflammatory drugs [NSAIDs], or anti-diabetic and anti-hypertensive) compared to subjects untreated with these drugs.