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Lactoferrin (LTF) is an iron-binding protein canonically known for its innate and adaptive immune functions. LTF may also act as a tumor suppressor with antiproliferative action. LTFis inactivated genetically or epigenetically in various cancers, and a CpG island spanning the transcriptional start site of LTFis hypermethylated in prostate cancer cell lines. We, therefore, hypothesized that LTF expression is silenced via CpG island hypermethylation in the early stages of prostate tumorigenesis carcinogenesis. Targeted methylation analysis was performed using a combination of methylated-DNA precipitation and methylation-sensitive restriction enzymes, and laser-capture microdissection followed by bisulfite sequencing on DNA isolated from prostate tissue samples, including both primary and metastatic disease. LTFmRNA in situhybridization and LTF protein immunohistochemistry were also performed. We report that the LTFCpG island is frequently and densely methylated in high-grade prostatic intraepithelial neoplasia, primary prostate carcinoma, and metastases. We further report a decoupling of lactoferrin mRNA and protein expression, including in lesions where LTFmRNA has presumably been silenced via CpG island methylation. We conclude that LTFmRNA expression is silenced in prostate tumorigenesis via hypermethylation, supporting a role for LTFas a prostate cancer tumor suppressor gene. Likewise, the frequency at which the LTFCpG island is methylated across samples suggests it is an important and conserved step in prostate cancer initiation.