HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic, progressive neurological disorder and shares many radiological and clinical features with other more prevalent myelopathies. Here, we quantified spinal cord and brain volumes in adults with HAM/TSP in comparison with healthy volunteers (HVs) and individuals diagnosed with relapsing–remitting or progressive multiple sclerosis (RRMS or P-MS). Clinical disability and MRI were assessed in 24 HVs, 43 HAM/TSP subjects, and 46 MS subjects. Spinal cord cross-sectional area (SCCSA) and brain tissue volumes were measured and compared. HAM/TSP subjects had significantly lower SCCSA corresponding to cervical levels 2 and 3 (C2–3) (54.0 ± 8 mm2), cervical levels 4 and 5 (C4–5) (57.8 ± 8 mm2), and thoracic levels 4 to 9 (T4–9) (22.7 ± 4 mm2) and significantly elevated brain white matter hyperintensity (WMH) fraction (0.004 ± 0.008) compared to the HVs (C2–3: 69.4 ± 8 mm2, C4–5: 75.1 ± 9 mm2, T4–9: 34.1 ± 4 mm2; all p p 2, C4–5: 72.7 ± 9 mm2, T4–9: 33.4 ± 5 mm2; all p p = 0.0067). Principal component analysis suggested that SCCSA and WMH may be used to differentiate HAM/TSP from MS. Understanding these differences msay help establish early diagnostic criteria for HAM/TSP patients.