Introduction: Wilson disease (WD) is an inborn error of copper metabolism (OMIM #277900) caused by the recessive genetic defects in the P-type copper-transporting ATPase. The clinical courses of WD patients with neurological manifestations are more indolent and less favorable than those with hepatic dysfunction and without neurological manifestations. In the current study, we investigated the biochemical and molecular genetic features of WD with neurological manifestations to identify that these WD patients’ group is a distinct phenotypic or genetic group among WD patients. Methods: We evaluated the detailed biochemical profiles and genotypic characteristics between WD patients with neurological presentation and without neurological manifestations in total of 379 WD patients from 368 unrelated families. Results: Eighty-six (22.7%) patients showed neurological manifestations, of whom over 70% patients showed basal ganglia abnormalities and typical symptoms. Compared with patients in the hepatic subgroup, patients in the neurological subgroup had a later age at onset, a higher proportion with Kayser-Fleischer rings, and higher serum creatinine levels, and a lower proportion with favorable outcome (62% vs. 80%, P 0.016). At diagnosis, the neurological subgroup had lower serum ceruloplasmin (3.1 ± 2.1 vs. 4.2 ± 3.2 mg/dL, P 0.001), total copper (26.4 ± 13.8 vs. 35.8 ± 42.4 μg/dL, P = 0.005), free copper (17.2 ± 12.5 vs. 23.5 ± 38.2 μg/dL, P = 0.038), and urinary copper (280.9 ± 162.9 vs. 611.1 ± 1124.2 μg/day, P 0.001) levels. Serum aspartate aminotransferase, alanine aminotransferase, gamma glutamyltransferase, and total bilirubin levels as well as prothrombin time were also lower in the neurological subgroup. Liver cirrhosis was more common but mostly compensated in neurological subgroup. Frameshift, nonsense, or splice-site ATP7B mutations and mutations in transduction or ATP hinge domains (2.5% vs. 22%, P = 0.01) were less common in the neurological subgroup. Conclusions: The different biochemical profiles representing either hepatic dysfunction or defective copper metabolism along with different mutation spectrum characterize the WD patients with neurological manifestations as a distinct phenotypic subgroup. Unknown factors might underlie this subgroup either in association with or without copper metabolism.