NOD-like receptor pyrin domain-containing 3 (NLRP3) has been considered to play a crucial role in triggering the host's immune and inflammatory responses. Genetic variants are critical determinants of interindividual variances in inflammatory responses and clinical outcomes. The role of NLRP3 gene variations in bipolar I (BPI) disorder, which is known to include genetic factors in its aetiology, has not been previously reported, at least to the best of our knowledge. The present study aimed to determine the role and frequency ofta exon 2 and exon 3 variants of NLRP3 in BPI disorder and to evaluate the association between different phenotypic traits. A case-control study with 123 patients and 107 healthy controls was conducted to investigate the association of variants identified in the exon 2 and exon 3 regions of NLRP3, with the risk of BPI. Regions of interest were sequenced using a PCR-based Sanger sequencing method. Three BPI-related variants were identified. The genotype Q705K CA was detected more frequently in BPI patients, as compared to the control group [P<0.001; odds ratio (OR), 0.202; 95% confidence interval (CI), 0.080-0.508]. In addition, two novel splice-site variants (c.393G>A and c.278_2A>G) that, to the best of our knowledge, have not been previously reported in any database, were detected only in the BPI patient group [P<0.001; OR, 0.846; 95% CI, 0.784-0.912; P<0.001; OR, 0.886; 95% CI, 0.832-0.944, respectively]. There was no significant association between the Q795K variant and phenotypic traits (P>0.05). However, there was a significant association between those carrying the heterozygous c.393G>A variant and a positive family history (P=0.043). It was also observed that those with the heterozygous c.278-2A>G variant presented with a significantly early-onset (P=0.003). On the whole, the data of the present study suggested that NLRP3 plays a crucial role in the pathogenesis of BPI and may be a potential risk factor. However, further functional studies and repeated studies in other populations are required to properly comprehend the roles of the NLRP3 variants in the risk of developing BPI.