Human T-cell lymphotropic virus type I (HTLV-I) infection is associated with a variety of human diseases including HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP), a chronic progressive inflammatory neurological disease. An important risk factor for the development of HAM/TSP is thought to be a high HTLV-I proviral load. Histopathological studies have demonstrated the presence of HTLV-I virus in the affected areas of spinal cords from HAM/TSP patients. Furthermore, T-cell infiltrations have been shown in spinal cord lesions. The precise mechanism for disease development is still unknown. Virus-host immune interactions are considered to play an important role in disease pathogenesis. This review focuses on current molecular, histopathological, and immunological approaches to understand the immunopathogenesis of HAM/TSP.