More than 6 million deaths have been attributed to COVID-19, primarily arising from acute respiratory failure [7]. Recent data indicate that disease severity predominantly depends on host factors [8, 9], supporting the need to better differentiate individual responses at the molecular level. We and others have described outcome-specific multi-omic profiles of COVID-19 patients [4, 5, 10]. However, specific host mechanisms that coordinate expression of these profiles are unresolved. While an individual’s nucleated cells share identical genomic sequences, distinct cellular phenotypes are established and maintained by epigenetic mechanisms [11, 12], including DNA methylation, histone and chromatin modifications, and non-coding RNA transcription [2]. DNA methylation regulates gene expression and is sensitive to environmental factors [2, 13,14,15,16,17]. Methylation of CpGs located in promoter regions is canonically associated with transcriptional repression [2]. Mechanistically, methylated CpGs recruit complexes containing methyl-CpG binding domain proteins and other factors that aggregate into multiprotein repressive complexes to silence transcription [18, 19]. Critically ill patients have altered circulating blood DNA methylation profiles [20, 21], consistent with epigenetic regulation of gene expression. We have recently reported a genome-wide DNA methylation analysis of patients with COVID-19 in correlation with clinical outcomes spanning full recovery to death, and multiple sources have reported that DNA methylation is relevant in the pathophysiology of acute COVID-19 infection [22,23,24]. These findings introduce evidence of acute epigenetic regulation of genes associated with COVID-19 severity [4]. Although many patients who survive COVID-19 develop long-term cognitive and somatic dysfunctions [25], no pathobiological processes that account for these lingering deficits have been identified. We present here evidence that epigenetic marks can persist beyond clinical resolution of acute illness. These data are the first reported evidence that DNA methylation changes in circulating leukocytes endure at least 1 year after recovery from acute COVID-19 illness, leaving durable marks in the methylome that may condition patterns of gene expression that drive PASC pathophysiology. Accordingly, DNA methylation may be a mechanism regulating leukocyte adhesion and vascular injury and contribute to the recently described higher risk of cardiovascular events after COVID-19 [1]. A limitation of our study is that the age difference between the healthy, pre-pandemic, and the SARS-CoV-2 cohorts. Interestingly, recent evidence indicates that epigenetic clocks are not accelerated by acute COVID-19 infection [26], and the comparison between epigenetic and chronological ages in our cohort has been found not significant [4]. Other limitations of this study include the use of a DNA methylation detection platform that targets a limited number of CpGs (~4% of CpGs in the entire methylome) and the relatively small cohort size. Future studies comprising larger cohorts and whole-genome methylation and RNA sequencing may serve to further identify regions and transcripts that associate with, and predict, PASC phenotypes and that contribute to disabling COVID-19 sequelae.