Neuropsychiatric manifestations are uncommon adverse events in patients with rheumatic diseases, when treated with chloroquine (CQ) or hydroxychloroquine (HCQ). This possibility is related to their ability to cross the blood-brain barrier ; in the brain, they have a tissue concentration up to10-20 times higher than the plasmatic one. A great variety of neuropsychiatric side effects was referred to CQ/HCQ; in some cases, they caused the patient' s hospitalization or death. Personal previous psychiatric symptoms, family history, female gender, alcohol intake, co-exposure with some drugs ( including low doses of glucocorticoids) , a dose >6.5 for HCQ and >3 mg/kg/day for CQ, are the most important risk factors. No difference between older and younger patients was found but polypharmacology and age-related renal impairment, can increase the risk in older ones. Differential diagnosis between pharmacological side effects and neuropsychiatric manifestations of the rheumatic disease is mandatory.