Background <p>HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic inflammatory disease of the central nervous system (CNS). Teriflunomide is an oral agent developed for the treatment of multiple sclerosis (MS) by suppressing the proliferation of autoreactive lymphocytes. This study was conducted to evaluate the efficacy of teriflunomide in HAM/TSP patients in Northeast Iran.</p> Methods <p>This study was a triple-blind, randomized, placebo-controlled trial involving 22 patients with HAM/TSP. The intervention group (<i>n</i> = 11) received one tablet of teriflunomide (14 mg daily), while the control group (<i>n</i> = 11) received one placebo tablet for 12 months. Muscle strength, spasticity, motor disability, urinary disorders, walking speed, laboratory factors, and drug complications were examined during the study.</p> Results <p>In the intervention group, consumption of teriflunomide decreased the duration of walking according to the T25FW test (<i>p</i> = 0.01). The severity of OMDS disability also significantly decreased (<i>P</i> &lt; 0.001). Additionally, the total score of UDS in the intervention group decreased. The levels of HTLV-1 proviral load significantly decreased (<i>p</i> = 0.003). No adverse effects were observed, and the increase in liver enzyme levels was tolerable and controllable.</p> Conclusions <p>Teriflunomide effectively reduced the proviral load, improved the severity of disability and walking speed, and better controlled urinary and constipation symptoms without any adverse effects. Therefore, teriflunomide can be considered a disease-modifying therapy for patients with HAM/TSP. However, further studies with a large number of patients and longer duration, along with the determination of specific HAM/TSP-associated biomarkers, are needed to validate the results of the present study.</p> Trial registration <p>IRCT20180618040127N3; November 19, 2021.</p>