Osteosarcoma is a common malignant tumor, which exists widely in the bone of children and adolescents. Protein kinase C gamma (PRKCG) gene, which encodes γPKC, plays important roles in tumor promotion, cell proliferation, differentiation, and migration. The objective of the present study was to investigate the relationship between PRKCG polymorphisms and the risk of osteosarcoma. Five tag single nucleotide polymorphisms (SNPs) of PRKCG were retrieved from the HapMap database and genotyped by the method of SNapShot in a hospital-based study containing 388 patients and 388 healthy individuals. Odds ratios (ORs) and their 95 % confidence intervals (CIs) were used to evaluate the association SPSS 20.0 statistical software package was used to analyze statistical data. Our results suggested that the T/C variant of rs454006 located in the intron 3 region of PRKCG gene was significantly associated with an increased risk of osteosarcoma (CC vs. TT, OR = 1.91; 95 % CI 1.29-2.85; P = 0.001; CC vs. TT+TC, OR = 2.14, 95 % CI = 1.48-3.09, P = 0.001; C vs. T, OR = 1.32, 95 % CI = 1.08-1.62, P = 0.008). Similarly, the rs3745406 T/C variant can also elevate the risk of osteosarcoma in the dominant model (OR = 1.45, 95 % CI = 1.08-1.96, P = 0.014), homozygous model (OR = 1.68, 95 % CI = 1.10-2.59, P = 0.002), and allelic model (OR = 1.31, 95 % CI = 1.07-1.61, P = 0.009). However, there were no significant differences in genotypes and allele frequencies of rs2547362 (T>C), rs8103851 (C>G), and rs2242245 (T>C) SNPs between osteosarcoma patients and healthy controls. The results showed that carrier of rs454006*C allele and rs3745406*C might elevate the risk of osteosarcoma. Further studies are needed to validate the coalition between PRKCG gene polymorphisms and risk of osteosarcoma relying on a larger population that included the participants in different ethnicity and hospital.