Previously, we have reported frequent silencing of the expression of LRP1B by genetic and epigenetic mechanisms in esophageal squamous cell carcinoma. As the same events might be involved in the development/progression of OSCC, we examined intragenic homozygous deletions, expression levels, and methylation status in the CpG island of this gene. Homozygous deletion was detected in only 1 of 18 (5.6%) OSCC lines, whereas the expression of LRP1B mRNA was silenced in 8 of 17 (47.1%) OSCC lines without homozygous deletion. An inverse correlation between mRNA expression and methylation status of the LRP1B CpG island was clearly observed in OSCC lines, and LRP1B mRNA expression was restored by treatment with 5-aza-dCyd. Frequent methylation of the LRP1B promoter was also observed in primary OSCC. Taken together, the results suggested that frequent inactivation of LRP1B mainly occurs by means of epigenetic mechanisms in OSCC, which might play an important role in oral tumorigenesis.