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<i>Leptin</i> (<i>LEP</i>) regulates glucose metabolism and energy storage in the body. Osteoarthritis (OA) is associated with the upregulation of serum <i>LEP</i>. <i>LEP</i> promoter methylation is associated with obesity. So far, few studies have explored the association of BMI and OA with <i>LEP</i> methylation. We assessed the interaction between body mass index (BMI) and OA on <i>LEP</i> promoter methylation. Data of 1114 participants comprising 583 men and 558 women, aged 30&#8722;70 years were retrieved from the Taiwan Biobank Database (2008&#8722;2015). Osteoarthritis was self-reported and cases were those who reported having ever been clinically diagnosed with osteoarthritis. BMI was categorized into underweight, normal weight, overweight, and obesity. The mean <i>LEP</i> promoter methylation level in individuals with osteoarthritis was 0.5509 &#177; 0.00437 and 0.5375 &#177; 0.00101 in those without osteoarthritis. The interaction between osteoarthritis and BMI on <i>LEP</i> promoter methylation was significant (<i>p</i>-value = 0.0180). With normal BMI as the reference, the mean <i>LEP</i> promoter methylation level was significantly higher in obese osteoarthritic individuals (<i>&#946;</i> = 0.03696, <i>p</i>-value = 0.0187). However, there was no significant association between BMI and <i>LEP</i> promoter methylation in individuals without osteoarthritis, regardless of BMI. In conclusion, only obesity was significantly associated with <i>LEP</i> promoter methylation (higher levels) specifically in osteoarthritic patients.