Disruption of the Catechol-O-methyltransferase (COMT) gene has been shown to be involved in pre-eclampsia (PE). To investigate whether two promoters of the COMT gene are differentially regulated by methylation in PE patients, we have analyzed the genomic DNA extracted from placenta (cases n = 16; controls n = 21), maternal peripheral blood (cases n = 4; controls n = 6) and umbilical cord blood (cases n = 8; controls n = 8) of women with PE and women with normal pregnancy. Bisulfite sequencing identified the predominantly unmethylated MB-COMT promoter in placenta, maternal peripheral blood and umbilical cord blood samples (PE and control). Subsequent quantitative MassArray data confirmed a significant tissue-specific hypomethylation of the S-COMT promoter in placenta (mean = 28.6%) when compared with its densely methylated patterns in blood samples (mean = 74.5%, P < 0.001), consistent with the sequencing data. However, no PE-specific methylation difference was found between cases and controls either in placenta or in blood samples. Moreover, none of the clinical characteristics had an effect on the methylation status of the S-COMT promoter. This study does not support a causal link between methylation regulation of COMT promoters and PE. However, the observed placenta-specific S-COMT promoter may be a potential marker for early prediction of PE in maternal plasma, although this remains to be further evaluated.