Objective: Although a few of case reports and two case-controls studies were available, the data regarding the risk of neuroleptic malignant syndrome (NMS) associated with the use of antipsychotic, particularly the potency of Dopamine 2 (D2) inhibitions, and other risk factors is limited. It aims to examine the risk of NMS associated with the use of antipsychotic, in particular potency of D2 inhibition, and other risk factors. Methods: A retrospective, population-based case-control study is performed using a managed care medical claims database. Among 154,474 patients with bipolar disorder, a total of 50 cases with NMS during the study period are identified and matched with 800 controls by age, and the year of the index date of bipolar disorder. Antipsychotics are grouped based upon the potency of D2 receptor that is measured by Ki values. Persons with ever other antipsychoitcs (except the high-potency antipsychotics) prescribed are then defined as low-potency antipsychotic users (Ki= 1 nM). Results: The use of antipsychotic is associated with a 2.36-fold increased risk of NMS after controlling the other risk factors (95% confidence interval [CI]=1.08 to 5.19). Besides the use of antipsychotic, being male is associated with a 2-fold increased risk of NMS. Other risk factors, including the previous history of delirium, confusion, dehydration, and extrapyramdial signs, can significantly increase the risk of NMS . The adjusted ORs for the patients with the use of low-potency antipsychotics and high-potency antipsychotics are 1.47 (95%CI=0.49 to 4.42), and 3.91 (95%CI=1.38 to 11.14), respectively, as compared to non-users. Conclusion: Besides the use of antipsychotic, other factors including being male, presence of delirium, confusion, dehydration, and extrapyramdial signs could significantly increase the risk of NMS. The magnitude of the risk of NMS seems to be related to an antipsychotic' potency of D2 inhibition.