Background: In recent decades, the assessment of neurological soft signs (NSS) in patients with psychosis has become a subject of special interest. The study of the progression of NSS during adolescence will provide valuable information about the role of NSS as endophenotypes or biomarkers and about brain development at a stage in which brain maturation has not yet been completed. Methods: Neurological soft signs were assessed in a sample of 110 first episodes of early-onset psychosis (EOP) and 98 healthy children and adolescents at two different times in a 2-year follow-up period. Results: Patients with EOP showed more NSS than controls both at baseline (p less than 0.001) and the 2-year follow-up (p less than 0.001). No differences were found in the number of signs among the different diagnostic subgroups (schizophrenia, bipolar disorder, and other psychoses). When we examined the changes in NSS over the follow-up, the reduction of NSS in the patients was greater than the controls for "Motor coordination" (p = 0.032), "Others" (p less than 0.001), and "Total score" (p less than 0.001) of the NES. Conclusion: Despite the greater reduction of NSS in patients than in controls along the follow-up, patients still have more neurological signs than healthy controls; therefore, these signs may be considered a trait marker. NSS do not seem to be specific to schizophrenia as they are present in different EOPs.