People with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) often report a high frequency of viral infections and flu-like symptoms during their disease course. Since this reporting is in line with different immunological abnormalities and altered gene expression profiles observed in the disease, we aimed to explore whether the expression of the human angiotensin-converting enzyme-2 (ACE2), the major cell entry receptor for SARS-CoV-2, is also altered in this neglected clinical population. In particular, a low expression of
ACE2
is usually indicative of a high risk of developing COVID-19. We then performed a meta-analysis of public data on CpG DNA methylation and gene expression of this enzyme and its homologous ACE protein in peripheral blood mononuclear cells and related subsets. We found that patients with ME/CFS have decreased methylation levels of four CpG probes in the
ACE
locus (cg09920557, cg19802564, cg21094739, and cg10468385) and of another probe in the promoter region of the
ACE2
gene (cg08559914). We also found a decreased expression of
ACE2
but not of
ACE
in patients with ME/CFS when compared to healthy controls. Accordingly, in newly collected data, we found evidence for a higher proportion of samples with an
ACE2
expression below the limit of detection in patients with ME/CFS than in healthy controls. Altogether, patients with ME/CFS could be at a higher COVID-19 risk when infected by SARS-CoV-2. To further support this conclusion, similar research should be conducted for other human cell entry receptors and other cell types, namely, those mainly targeted by the virus.