Abstract A regulatory single nucleotide polymorphism located in the 5′ region (−169T/C) of the Fc receptor-like 3 (FCRL3_3) gene has been associated with both susceptibility and protection in immune diseases. This case–control study aimed to evaluate the association between FCRL3 polymorphisms and juvenile rheumatoid arthritis (JRA), asthma, and childhood-onset systemic lupus erythematosus (SLE) in a Mexican population. We performed PCR-based genotyping to identify four FCRL3 single nucleotide polymorphisms (FCRL3_3 to FCRL3_6) in patients with JRA (n=202), asthma (n=239), or childhood-onset SLE (n=377), and healthy controls (n=400). The case–control analysis showed a male-gender dependent association between the FCRL3_3C, FCRL3_5C, and FCRL3_6A alleles and either JRA (OR=0.57, p=0.003; OR=0.55, p=0.002; OR=0.53, p=0.0007, respectively) or asthma (OR=0.72, p=0.04; OR=0.74, p=0.05; OR=0.70, p=0.02, respectively). As expected, minor alleles of these SNPs with the CGCA haplotype were also significantly associated with JRA (OR=0.35, p=0.00005) and asthma (OR=0.61, p=0.007). We found no association between FCRL3 SNPs or haplotypes and childhood-onset SLE. These results supported the notion that FCRL3 is involved in the etiology of several immune diseases. Our results also suggested that SNPs located in the FCRL3 gene were protective against JRA and asthma in male Mexican patients.