Zuclopenthixol acetate is an injectable depot antipsychotic that is effective for 24-48 hours and mainly used for the treatment of acute mania or psychotic episodes. To our knowledge, there is only one case report reporting edema after zuclopenthixol use, which described a patient had suffered from facial and peripheral edema after zuclopenthixol decanoate injection. Here, we present a patient with bipolar disorder who developed bilateral pretibial edema following repeated zuclopenthixol acetate injections. A 53-year-old male patient with no previous medical history presented with manic symptoms. Based on his past psychiatric treatment history, zuclopenthixol acetate was initiated, and three positive pretibial edema developed bilaterally after administration. Although no pathological findings to explain edema were detected, the Naranjo Adverse Reaction Probability Scale showed a “probable” relationship of zuclopenthixol and edema with a score of 8. Peripheral edema may develop due to various common medical conditions including antipsychotic drugs and can be life-threatening. Although the exact mechanisms of peripheral edema due to antipsychotic use are still unknown, further studies may shed further light on these mechanisms.