The patterns of HLA genetic variation worldwide show significant information about human geographic expansion, demographic history and cultural diversification. Here we investigate the contribution of HLA alleles and haplotypes in a scenario where also uniparental markers (mitochondrial DNA, mtDNA, and Y-chromosome, MSY) are considered. We analyzed the offspring DNA samples of 46 families from Venezuela, testing 32 and 20 unrelated individuals for mt-DNA and for MSY, respectively. 25 were assigned to Native American (A2 n=4, A2am n=2, A2k1a n=1, B2 n=1, B2b n=1, B2d n=4, B2e n=1, B2j n=2, C1b n=3, C1c n=1, C1d n=1, C1d1 n=1, D1f1 n=1, D1f2 n=1, D4h3a n=1) and 7 to European and African mtDNA haplogroups (H n=5, L2a1a2 n=1 and T2b n=1). For MSY, one belonged to the Native American haplogroup Q, while 10, 6 and 3 were assigned to R1b, E and J non–native haplogroups, respectively. Allele-level typing was available for HLA-A,-B,-C,-DRB1,-DQA1,-DQB1 and -DPB1, including the definition of maternal/paternal inherited haplotypes (MIH/PIH). We examined HLA alleles and haplotypes of our sample compared to the Sierra de Perija Yucpa and Bari. We found several alleles frequent in Venezuelan Amerindians, such as A*02:13 (n=2), A*02:04 (n=3) and B*35:43 (n=4). We also found characteristic DPB1 alleles, such as *04:02 (n=15) and *14:01 (n=7), native DQA1*03:01-DQB1*03:02 haplotype in 12 samples (60.6% in Venezuelan Amerindians), and native DQA1*04:01-DQB1*04:02 haplotype (12.8% in Venezuelan Amerindians) associated to DRB1*08 in 7 samples. Interestingly, A*02:04-B*35:43-DRB1*04:07 in the PIH was associated to non-native MSY haplogroup R1b. Moreover, the sample assigned to non-native mt-DNA haplogroup H showed native DRB1*04:03-DQA1*03:01-DQB1*03:02 (11.7% in Yucpa) in the MIH, while the sample belonging to MSY haplogroup Q showed a non-native HLA PIH. HLA polymorphism could be complementary to uniparental markers, especially when parental inherited haplotypes are defined, providing a useful tool for anthropological studies.