Tuberculosis (TB) is a major and severe opportunistic infection among solid organ transplant recipients. Chemoprophylaxis is advised for those with latent tuberculosis infection (LTBI). However, the effectiveness of an isoniazid (INH) prophylactic approach based on TB risk factors remains uncertain. This study included all living-donor kidney transplant recipients (KTRs) between January 2016 and December 2022. The recipients were categorized into three groups: the risk group with isoniazid (R-INH), the risk group without isoniazid (R-NINH), and the non-risk group (NR), based on the presence of TB risk factors and INH usage. The R-INH group received a 6-month INH prophylactic regimen to prevent post-transplant TB infection. The incidence of active TB among the groups was assessed. A total of 1348 patients were divided into R-INH (n=108), R-NINH (n=371), and NR (n=869). Forty-seven patients (3.49%) developed TB with an incidence rate of 16.0 per 1000 person-years. Compared to NR, the TB incidence in R-INH was not statistically different (HR, 0.55, 95% CI, 0.07-4.21, P = 0.564), whereas it was significantly higher in R-NINH (HR, 5.04, 95% CI, 2.64-9.62, P < 0.001). The median time from transplantation to TB was 19 months (IQR: 6-39), and 18 patients (38.3%) were diagnosed within one year of transplantation. Ninety-four patients (87.0%) completed INH prophylaxis, with adverse events including two cases of hepatotoxicity (1.85%) and one case of peripheral neuritis (0.93%). A 6-month INH regimen based on TB risk factors is effective and well tolerated for preventing post-transplant TB in KTRs.