To evaluate the hypothesis that human leukocyte antigens (HLAs) confer susceptibility to schizophrenic disorders, by assessing their contribution to the risk of schizophrenia in a Yemeni population. Methods: The researchers approached patients who had been diagnosed with schizophrenia at Al-Amal Hospital for Psychiatric Diseases, Sana’a. Controls were drawn randomly from the general population. The HLA class II alleles of the participants were examined. The genotypes of the HLA-DQB1 and HLADRB1 alleles were determined by polymerase chain reaction using sequence-specific primers. Results: The subjects comprised 110 patients with schizophrenia, matched by an equal number of controls. The prevalence of HLA-DRB1*04 was significantly higher among patients than among controls (7.3% vs. 0.0%; p = 0.003), as was HLADRB1*07 (62.7% vs. 17.3%, odds ratio (OR) = 8.1, 95% CI: 4.3–15.1; p 0.001). HLADRBI*14 was significantly less prevalent among patients (0.9% vs. 11.8%, OR = 0.06, 95% CI: 0.01–0.50, χ2 = 10.9; p 0.001). HLA-DQB1*07 was the most common allele discovered in schizophrenia patients and was found to have a much higher incidence in patients than the control group (22.7% vs. 4.5%, OR = 6.2, 95%CI: 2.3–16.8, χ2 = 15.4; p 0.001). Conclusions: The HLA-DQB1 and HLA-DRB1 gene loci are linked to schizophrenia in the Yemeni population, according to the current study’s evidence.