The heritability levels of two traits for diabetes diagnosis, serum fasting glucose (FG) and glycated hemoglobin (HbA1c), were estimated to be 51–62%. Studies have shown that cigarette smoking is a modifiable risk factor for diabetes. It is important to uncover whether smoking may modify the genetic risk of diabetes. This study in-cluded unrelated Taiwan Biobank subjects in a discovery cohort (TWB1) of 25,460 subjects and a replication cohort (TWB2) of 58,774 subjects. Genetic risk score (GRS) of each TWB2 subject was calculated with weights retrieved from the TWB1 analyses. We then assessed the significance of GRS-smoking interactions on FG, HbA1c, and diabetes while adjusting for covariates. A total of five smoking measurements were investigated, including active smoking status, pack-years, years as a smoker, packs smoked per day, and hours as a passive smoker per week. Except for passive smoking, all smoking measurements were associated with FG, HbA1c, and diabetes (P < 0.0033) and were associated with an exacerbation of the genetic risk of FG and HbA1c (PInteraction < 0.0033). For example, each 1 SD increase in GRS is associated with a 1.68% higher FG in subjects consuming one more pack of cigarettes per day (PInteraction = 1.9 ☓ 10–7). Smoking cessation is especially important for people who are more genetically predisposed to diabetes.