The present study was aimed to investigate the relationship between NOD1/CARD4 and NOD2/CARD15 gene polymorphisms and osteoporosis in the Turkish population. The first time we thought that the functional polymorphisms in NOD1/CARD4 and NOD2/CARD15 genes might have triggered the development of osteoporosis. The objective of our study was to determine the relationship between NOD1/CARD4 and NOD2/CARD15 SNPs and osteoporosis. The NOD1/CARD4 (rs5743336) and NOD2/CARD15 (rs2066847) SNPs were analyzed by PCR restriction fragment length polymorphism (PCR-RFLP) in 94 healthy controls and 164 subjects with osteoporosis. PCR products were digested with restriction enzymes AvaI for NOD1/CARD4 and ApaI for NOD2/CARD15. We found that NOD1/CARD4 genotype distribution of AA, GA and GG were 15, 44 and 41% for patients and 17, 46 and 37% for controls, respectively. NOD2/CARD15 mutation was found only in three patients (1.8%) as heterozygote. The results did not show any statistical difference between NOD1/CARD4 and NOD2/CARD15 genotype distribution of patients and healthy groups (χ2 = 1.740, P=0.187; χ2 = 1.311, P=0.519). However, the most frequent AG genotype (46%) of NOD1/CARD4 was observed in healthy controls, GG genotype (44%) of NOD1/CARD4 was observed as the most frequent in osteoporotic patients. NOD2/CARD15 WT/WT genotype, the most frequent genotype, was observed in both groups. Statistical analysis revealed that NOD1/CARD4 and NOD2/CARD15 polymorphisms are not associated with osteoporosis. However, a definite judgement is difficult to be made due to restricted number of patients and small size of control group. Further research is sorely warranted in this direction.