Neuropsychiatric disorders are associated with neurological soft signs (NSS), including motor, sensory, and inhibitory dysfunction. The present study aims at determining the prevalence of NSS and explore the association of sociodemographic characteristics with the occurrence of NSS in patients with bipolar disorder and unipolar depression compared to healthy controls. A case-control study included a sample of 50 bipolar and unipolar patients and 50 healthy controls. NSS subscales of the Neurological Evaluation Scale (NES) were administered to each participant. Significant differences were found in the total NES score, motor coordination, sensory integration, sequence of complex motor act and other subscales among the three groups. Compared with healthy controls, patients with bipolar disorder showed significantly more total NSS signs, motor coordination signs and sensory-integration signs. When compared with patients with unipolar disorder, patients with bipolar disorder showed significantly more sensory integration signs and a trend of difference in the sequencing of complex motor acts and other subscales. Our findings suggest that NSS may be specifically associated with bipolar disorder but not unipolar depression. The specificity of NSS expression has the potential to help the discrimination of bipolar disorder from disorders less likely to have a neurodevelopmental component such as major depression.