We conducted a case-control study aimed at identifying polymorphisms and haplotypes in the FcepsilonRIbeta gene associated with asthma and its associated phenotypes such as serum IgE levels. A G/A polymorphism in intron 2, a (CA)n repeat polymorphism in intron 5, and a C/T polymorphism in 3'-UTR, encompassing a length of 8.74 Kb, were genotyped, and haplotypes were generated for unrelated patients and healthy volunteers in two independent cohorts. A significant association was observed at the level of alleles and genotypes studied with asthma independently in the two cohorts (p < 0.05). A change in CC_AA genotype combination to a non-CC_AA genotype was associated with reduced risk for asthma. Interestingly, a three-locus haplotype, A_16_C, was found to be significantly associated with asthma (p = 10(-5) in cohort A and p = 0.004 in cohort B). On the other hand, the haplotype G_18_T was found to be negatively associated with asthma (p = 0.007 in cohort A and p = 0.0004 in cohort B). This is the first study identifying a haplotype A_16_C that predisposes individuals to asthma in the Indian population.