Psychomotor performance has consistently been found to be altered in chronic cannabis users. Neurological soft signs (NSS) reflect neurological dysfunction involving integrative networks, especially those involving the cerebellum, where cannabinoid receptors are particularly concentrated. Our objective was to study, for the first time, NSS in a group of patients with cannabis dependence compared with a of healthy control subjects, matched for age, gender and level of education. All outpatients seeking treatment for chronic cannabis use in the substance abuse department of Sainte-Anne Hospital in Paris between June 2007 and May 2009 and meeting the cannabis dependence DSM-IV criteria were included in the study (n = 45). Patients with psychotic disorders, bipolar 1 disorder and current alcohol, opioid or cocaine dependence were excluded. All patients and controls were assessed using the Diagnostic Interview for Genetic Studies, which screens for lifetime DSM-IV diagnoses, and the Standardized Neurological Examination of Neurological Soft Signs. NSS scores were significantly higher in patients with cannabis dependence compared with healthy subjects (8.90 ± 4.85 versus 6.71 ± 2.73, respectively, Mann–Whitney: U = 775.0, P = 0.05). Patients had particularly high scores on motor coordination and sensory integration NSS factors. Cannabis dependence is associated with more NSS and especially motor coordination and sensory integration signs. These results suggest that cannabinoids interact with the brain networks underlying NSS, known to be altered in schizophrenia.