Diabetes is a major global public health problem worldwide caused by many factors including genetics and medication. Antihypertensive drugs had been reported to be associated with new-onset diabetes (NOD) in many countries, but not in Thai patients with hypertension. The purpose of this study was to investigate the association between antihypertensive drugs and NOD among Thai Isan patients. This retrospective cohort study obtained data from electronic medical records from community hospitals in Ubon Ratchathani from January 1, 2007 through December 31, 2015. Newly diagnosed hypertensive patients aged ≥ 20 years who received ACEI-based, thiazide-based and combined regimen were identified by ICD 10 code (I10 – I15) and were followed up for 6 years or diagnosed with NOD (E10 – E14). Propensity score was used as a covariate to control for confounding by indication bias due to non-randomly selection process during routine clinical treatment of hypertensive patients. Kaplan-Meier analysis and multivariate cox regression with propensity score adjustment were used to investigate the incidence and the risk of NOD. Of 3,689 newly diagnosed hypertension patients enrolled, 396 (10.73%) patients developed NOD during follow-up period. NOD incidence were 11.06 (95%CI, 9.19 – 13.27), 14.17 (95%CI, 12.48 – 16.05), and 14.17 (95%CI, 11.53 – 17.35) in ACEI-based, thiazide-based and combined regimen users respectively. After adjusting for confounding by indication, the Hazard Ratios were 1.540 (95%CI, 0.963 – 2.463) for thiazide-based regimen and 1.341 (95%CI, 0.769–2.338) for combined regimen compared to ACEI-based regimen. In conclusion, thiazide-based and combined regimen were not associated with NOD compared with ACEI-based regimen in Thai Isan patients.