Nasopharyngeal carcinoma (NPC) is a rare malignancy in most parts of the world. It is an Epstein-Barr virus-associated malignancy with an unusual racial and geographical distribution. The host innate immune sensor genes play an important role in infection recognition and immune response against viruses. Therefore, we examined the association between polymorphisms in genes within a group of pattern recognition receptors (including families of toll-like receptors, C-type lectin receptors, and RIG-I-like receptors) and NPC susceptibility. Twenty six single nucleotide polymorphisms (SNPs) in five pattern-recognition genes were genotyped in 492 North African NPC cases and 373 frequency-matched controls. TLR3_rs3775291 was the most significantly associated SNP (OR: 1.49; 95%CI: 1.11-2.00; P: 0.008; dominant model). The analysis showed also that CD209_rs7248637 (OR: 0.69; 95%CI: 0.52-0.93; P: 0.02; dominant model) and DDX58_rs56309110 (OR: 0.70; 95%CI: 0.51-0.98; P: 0.04) were associated with the risk of NPC. An 18% increased risk per allele was observed for the five most significantly associated SNPs, TLR3_rs3775291, CD209_rs7248637, DDX58_rs56309110, CD209_rs4804800 and MBL2_rs10824792, (ptrend 8.2x10-4). Our results suggest that genetic variation in pattern-recognition genes is associated with the risk of NPC. These preliminary findings require replication in larger studies.