Major histocompatibility complex class I chain-related gene (MIC) polymorphisms have been associated with many autoimmune diseases. To explore the correlation between MIC polymorphisms and systemic lupus erythematosus (SLE), we compared the sequence of the MIC gene in Han Chinese patients with SLE from Hainan Island, China, with healthy individuals. In this study, the MIC polymorphisms in 296 subjects (159 patients with SLE and 137 healthy volunteers) of Han ethnicity from Hainan Island were characterized. A chi-square test was performed to evaluate the differences in the allelic frequency of the MIC genes between patients with SLE and the control subjects. The genotyping results indicated that the frequencies of the MICA*010, MICB*014, and MICB*002 alleles were significantly higher in the control subjects than the patients with SLE. Additionally, the results also indicated that the frequency of the MICB*009N in the SLE group was significantly increased compared to that in the matched control subjects. The results of this study suggested that the MICB*009N allele might be a risk factor for SLE, whereas the MICB*014, MICA*010 and MICB*002 alleles were associated with reduced incidence of SLE in the study population.