OBJECTIVE: To explore the cerebrospinal fluid (CSF) proteome in systemic lupus erythematosus (SLE) and the associations between the CSF proteomic patterns and clinical manifestations. CSF samples from 29 female outpatients with SLE were analysed using label‑free LC–MS. Weighted gene co‑expression network analysis identified patient clusters and protein modules. Three clusters showed differing frequencies of nephritis, depression and cognitive dysfunction. Modules corresponding to neuronal proteins and macrophage proteins correlated with nephritis, depression and cognitive impairment, whereas modules enriched for plasma proteins and immunoglobulins correlated inversely with cognitive impairment. Patients clustered by their CSF proteomic pattern had distinct disease phenotypes, suggesting shared pathogenic pathways affecting the kidney and CNS.