T-box transcription factor protein (TBX21) is encoded by the TBX21 gene in human. It is crucial for naive T lymphocyte development, interferon-γ production, airway hyperresponsiveness and regulation of corticosteroid response in asthmatics. Polymorphisms rs4794067 and rs16947078 of TBX21 were found to be associated with acetylsalicylic acid-induced and allergic asthma, respectively. We examined whether sequence variants of TBX21 gene are associated with asthma and its severity in Indian population. In a hospital-based case-control study, 240 asthmatic children and 240 healthy controls were investigated for the association of TBX21 rs4794067 (C>T) and rs16947078 (G>A) polymorphisms with asthma and its severity using PCR-restriction fragment length polymorphism method. Heterozygous (CT) (odds ratio (OR)=2.33; P=0.001) and variant (TT) (OR=6.25; P=0.001) genotypes of rs4794067 were demonstrated significant risk of asthma. However, in asthma severity variant (TT) genotype revealed significant increase risk (intermittent: OR=5.9, P=0.001; mild: OR=8.0, P=0.001; moderate: OR=3.2, P=0.041; and severe: OR=43.6, P=0.001) in all subgroups. Furthermore, haplotypes TG (OR=2.83; P=0.001) and TA (OR=2.54; P=0.001) of TBX21 were associated with an increased risk of asthma. Conversely, rs16947078 G>A polymorphism was not associated with any asthma/asthma severity risk. These data suggest that TBX21 gene variation may modify individual's susceptibility to asthma and its severity in Indian population. However, further validation in large population-based studies is needed to confirm the finding.