DNA methylation is an epigenetic mark capable of modulating gene expression, and is influenced by a combination of genetics, environmental factors, and aging. Sex-specific methylation patterns are widespread across autosomal chromosomes and can be present from birth (i.e. sex-specific but not age-related) or arise over the lifespan (i.e. sex-specific and age-related). In individuals where gender identity and sex assigned at birth are incongruent, as in the case of transgender people, feminization or masculinization may be sought through gender affirming hormone therapy (GAHT). Previous studies have shown that periods of hormonal change, including puberty, pregnancy, and menopause, can affect blood methylation patterns, but GAHT-induced changes have not yet been fully characterized. We profiled genome-wide DNA methylation in blood of transgender women and transgender men prior to and after 6 and 12 months of GAHT. We identified several thousand differentially methylated CpG sites (DMPs) and several differentially methylated regions (DMRs) across both feminizing and masculinizing hormone therapy, with the majority showing progressive changes across GAHT. Genes with GAHT-associated DMPs in promoter regions were enriched for numerous immune and endocrine signaling processes. We found that sex-specific DNA methylation patterns already established at birth are largely refractory to GAHT-associated changes. GAHT did, however, alter a small proportion of sex-specific CpGs, with enrichment for age-related changes – and more specifically – adolescence-associated changes. Importantly, sex-specific CpGs altered by GAHT showed a consistent shift towards the methylation pattern of the GAHT-naïve opposite sex. These results provide novel insight into the effects of GAHT on the blood methylome and add perspective to the complex interplay of sex hormones, sex chromosomes, and DNA methylation in the context of immunity.