Background Lithium and quetiapine are considered standard maintenance agents for bipolar disorder yet it is unclear how their efficacy compares with each other. Aims To investigate the differential effect of lithium and quetiapine on symptoms of depression, mania, general functioning, global illness severity and quality of life in patients with recently stabilised first-episode mania. Method Maintenance trial of patients with first-episode mania stabilised on a combination of lithium and quetiapine, subsequently randomised to lithium or quetiapine monotherapy (up to 800 mg/day) and followed up for 1 year. (Trial registration: Australian and New Zealand Clinical Trials Registry - ACTRN12607000639426.) Results In total, 61 individuals were randomised. Within mixed-model repeated measures analyses, significant omnibus treatment6visit interactions were observed for measures of overall psychopathology, psychotic symptoms and functioning. Planned and post hoc comparisons further demonstrated the superiority of lithium treatment over quetiapine. Conclusions In people with first-episode mania treated with a combination of lithium and quetiapine, continuation treatment with lithium rather than quetiapine is superior in terms of mean levels of symptoms during a 1-year evolution.