Several case reports described neurotoxic side-effects in the course of a combined clozapine-lithium treatment. Here we report on the safety and efficacy of this combination in a sample of 44 hospital patients. Medical records were retrospectively audited and a subsample of 23 patients was re-assessed. Mean total duration of combined treatment was 23.5 months. The combination (indications: prophylaxis; treatment of affective symptoms or aggression/excitement; augmentation of neuroleptic efficacy) was rated effective in 84% and adverse events were reported in 64% of the patients. Notably, most of the adverse events were benign and transient. However, 8 patients (18%) developed transient neurological adverse events that were genuinely novel in only 3 patients (7%) and coincided with high dosage of medication or high plasma levels or serotonergic (antidepressant) co-medication. Our data suggest that combined clozapine-lithium treatment may appear to be safe and effective when administered within a moderate therapeutic dose range and without serotonergic co-medication or other substances interfering with clozapine metabolism.