Areca (betel) chewing is associated with the high incidence of oral squamous cell carcinoma (OSCC) and oral submucous fibrosis (OSF) in Asians. Heme oxygenase-1 (HO-1), encoding an oxidative response protein, plays protective roles in cells. A (GT)n microsatellite repeat in HO-1 promoter shows polymorphisms and modulates the level of gene transcription. We examined allelotypic frequencies of (GT)n repeats in 83 controls, 147 OSCC and 71 OSF. All subjects were male areca chewers. Logistic regression was used to adjust the age confounding for odds ratio (OR). (GT)n repeat polymorphism was classified into short (S), medium (M) and long (L) alleles. The adjusted OR in OSCC subjects carrying L allelotype relative to S allelotype was 1.75. Buccal squamous cell carcinoma (BSCC) is the most common OSCC subset in areca chewers. L allelotype implied the risk of BSCC with adjusted OR of 2.05, whereas M allelotype appeared protective for non-BSCC with adjusted OR of 0.49. Our findings indicated that longer (GT)n repeat allele in HO-1 promoter is associated with the risks of areca-related OSCC, while the shorter (GT)n repeat allele may have protective effects for OSCC.