Lithium has been proved to be highly efficacious in the treatment of bipolar affective disorder, though a narrow therapeutic index and a high incidence of troublesome side effects often leads to poor compliance in patients. Therefore, there is a need to explore treatment strategies to improve the efficacy and side effect profile of lithium. We compared the efficacy and side effect profile of a once-daily versus twice-daily dosing schedule of lithium in mania. Eighty-three manic patients according to International Classification of Diseases, 10th Revision, Diagnostic Criteria for Research, giving informed consent were randomly allocated to receive regular lithium carbonate once daily or twice daily. They were assessed using Bech-Rafaelsen Mania Rating Scale, a lithium side effect scale, hemogram, renal function test, lipid profile, and a thyroid function test at baseline and Day 7, Day 21, and Day 42. Repeated-measures analysis of variance for Bech-Rafaelsen Mania Rating Scale scores showed a significant main effect, but interaction of treatment groups over time was not significant. Those subjects receiving twice-daily lithium experienced significantly higher urinary frequency on Day 21 (P = 0.008) and Day 42 (P = 0.035). They also required significantly higher total daily dose of lithium (P = 0.017) and had lower serum lithium levels (P < 0.001). There was a significant positive correlation between urinary frequency at Day 42 with lithium dose. A twice-daily dose of lithium was of similar efficacy as the once-daily schedule but produces higher renal adverse effects that may be dose-related. Therefore, a single daily dose of lithium can be a viable method to reduce the side effects of lithium, which may lead to better patient compliance.