Genetic hereditary has been implicated in bipolar disorder pathogenesis. The PDLIM5 and HTR2A genes have been investigated for its association with bipolar disorder in various populations, however, the results have been conflicting. In this study, we investigate the association between bipolar disorder and the two genes of interest, PDLIM5 and HTR2A genes. We recruited 253 bipolar disorder patients (75 Malays, 104 Chinese, and 74 Indians) and 505 control individuals (198 Malays, 155 Chinese, and 152 Indians) from three ethnic groups within Malaysian population. We genotyped for 3 SNPs of the PDLIM5 (rs2433320, rs2433322 and rs2438146) and 3 SNPs of the HTR2A (rs6313, rs2070040 and rs6311). Significant associations between bipolar disorder and each of the 3 SNPs of PDLIM5 in Malays, Indians and pooled samples. However, only rs2438146 remains significant in the Malays as co-dominant (T/T vs. C/C, p=0.004, OR=0.128, 95%CI=0.031-0.524) and recessive genetic models (T/T vs. C/T+C/C, p=0.003, OR=0.122, 95%CI=0.030-0.494) after applying conservative Bonferroni correction. Haplotype analysis of 3 SNPs of PDLIM5 also showed a significant association with bipolar disorder. No association was observed between bipolar disorder and each of the 3 SNPs of HTR2A in any of the ethnicities. We conclude that PDLIM5 polymorphisms are associated with bipolar disorder in the pooled analysis. After stratification to different ethnic groups, the association remains significant in the Malay and Indian groups. The association is also supported by the significant association in haplotype analysis of PDLIM5. We also conclude there is no association between the HTR2A polymorphisms in the Malaysian population.