Objective To investigate the diagnostic and differential diagnostic strategies for new-onset muscle weakness occurring many years after poliomyelitis. Methods A comprehensive analysis was conducted on all clinical data from 3 patients with clear history of polio- myelitis who developed new-onset muscle weakness during hospitalization in the Department of Neurology at Peking University Third Hospital. Re- sults Two patients met the diagnostic key points of Post-Poliomyelitis Syndrome (PPS). In the third patient, clinical data, including clinical manifestations, neurophysiological examinations, and laboratory test results, met the diagnostic criteria for Amyotrophic Lateral Sclerosis (ALS), but did not support the key diagnostic points of PPS. Conclusions If survivors of poliomyelitis develop new-onset progressive muscle weakness, ALS must be actively ruled out; it cannot be simply attributed to PPS by default. Emphasis should be placed on the early differential diagnostic value of neurophysiological characteristics, tongue muscle ultrasound, and neurofilament light chain protein levels.