ABSTRACT: Testosterone deficiency (TD) is common and impairs quality of life (QoL) in patients with chronic kidney disease (CKD). However, there are no studies about whether testosterone replacement therapy (TRT) can improve QoL in patients with CKD. Therefore, we investigated the effect of TRT on the QoL of patients with CKD and confirmed the safety of TRT. Twenty-five male patients with stages III-IV CKD whose serum testosterone levels were <350 ng/dl (TD) were enrolled and treated with testosterone gel for 3 months (group II). Age-matched controls with stages III-IV CKD and TD (group I) were recommended to exercise for the same period. Before and after the treatment, the BMI and handgrip strength were checked, serological tests were performed, and questionnaires were administered in both groups. Compared to baseline, there was no significant difference in serum testosterone levels, scores of the 36-Item Short Form Health Survey (SF-36), Aging Males' Symptoms Scale (AMS), and International Prostate Symptom Score (IPSS), and grip strength in group I after 3 months. In group II, a significant increase in testosterone, hemoglobin (Hb), and hematocrit (Hct) was observed, and grip strength significantly increased after TRT. Significant improvement in scores of SF-36, AMS, and IPSS was also confirmed after TRT in group II. There was a significant difference in testosterone, Hb, Hct, grip strength, and scores of SF-36, AMS, and IPSS between the two groups after 3 months. The patients in group II showed positive results and continued with TRT. Therefore, we conclude that TRT safely improves the QoL and TD symptoms in patients with moderate-to-severe CKD.