Approximately four months after recovering from a mild COVID-19 infection, around 25% of individualsdeveloped visuoconstructive deficit (VCD), which was found to be correlated with an increase inperipheral immune markers and alterations in structural and metabolic brain imaging. Recently, it hasbeen demonstrated that supplemental vitamin B12 regulates hyperinflammation during moderate andsevere COVID-19 through methyl-dependent epigenetic mechanisms. Herein, whole peripheral bloodcultures were produced using samples obtained from patients with confirmed persistent VCD, andcontrols without impairment, between 10 and 16 months after mild COVID-19. This experimental modelwas used to assess the leukocyte expression patterns of 11 biomarkers previously associated with VCDin long COVID and explore the potential of pharmacological B12 in regulating these genes. The resultsshowed that patients with persistent VCD displayed continued upregulation of CCL11 and LIF comparedto controls. It is worth noting that elevated serum levels of CCL11 have been previously linked to age-related neurodegenerative diseases. Notably, the addition of 1 nM of vitamin B12 to blood cultures fromindividuals with VCD normalized the mRNA levels of CCL11, upregulated the neuroprotective HGF, and,to a lesser extent, downregulated CSF2 and CXCL10. There was an inverse correlation observed betweenCCL11 mRNA levels and methylation levels of specific cytosines in its promoter region. These findingsunderscore the significance of systemic inflammation in persistent VCD associated with long COVID.Moreover, the study provides evidence suggesting that B12, acting as an epidrug, shows promise as atherapeutic approach for addressing this cognitive impairment.