Previous studies suggest that in amyotrophic lateral sclerosis (ALS) the abductor pollicis brevis (APB) and first dorsal interosseous (FDI) are more severely involved than abductor digiti minimi (ADM). To elucidate the pattern, frequency, extent, and specificity of such dissociated muscle atrophy in ALS, compound muscle action potentials recorded from APB, FDI, and ADM were analyzed in 77 ALS patients, 171 normal controls, and 196 disease controls. Compared with normal controls, ALS patients had a reduced APB/ADM amplitude ratio (P < 0.001) and FDI/ADM ratio (P < 0.001), whereas patients with other anterior horn diseases showed similar APB/ADM and FDI/ADM ratios to normal values. Decreased APB/ADM ratio was found in 41% of ALS patients, 5% of normal controls, and 4% of disease controls. Prominent muscle atrophy in APB and FDI, with relatively preserved ADM, appears to be specific to ALS. Dissociated hand muscle atrophy presumably reflects part of the pathophysiology and supports the diagnosis of ALS.