Mycobacterium tuberculosis, the causal agent of pulmonary tuberculosis (TB), remains a major health problem throughout the world causing high mortality in humans. Previous studies showed that several genes may play crucial roles in susceptibility to TB. The PTPN22 gene encodes the lymphoid tyrosine phosphatase that has an important regulatory effect on T- and B-cell activation in immune response. The purpose of this study was to investigate the role of two functional missense single nucleotide polymorphisms (SNPs) of the PTPN22 gene region (R620W and R263Q) in the susceptibility to TB in the Moroccan population. A case-control association study was performed including 123 pulmonary TB patients and 155 healthy controls. All subjects were genotyped by TaqMan SNP genotyping assays. Regarding the PTPN22 R620W (C1858T) SNP, we observed a statistically significant difference in the distribution of the PTPN22 1885T allele between pulmonary TB patients and healthy controls (0.41% vs 3.2%, P = 0.01, odds ratio (OR) = 0.14, 95% confidence interval (CI) = 0.01-0.93). With respect to the PTPN22 R263Q (G788A), we observed an increase of 788A allele frequencies in TB patients compared with those in healthy controls (3.65% vs 0.65%, P = 0.01, OR = 5.85, 95% CI = 1.17-39.55). These results suggest that PTPN22 gene variants may affect susceptibility to TB in the Moroccan population.