Alzheimer's disease (AD) is a progressive neurodegenerative disorder affecting cognitive function. A number of allelic genes from HLA complex have shown variable associations with AD in different populations. In this study, we investigated the association of DQB106:00/x, DRB104:00/x, DRB115:00/x, and B07:00/x genotypes with AD and their relevance to the efficacy of rivastigmine treatment in the Iranian population. Our findings suggest that DQB106:00/x genotype offers strong protection against AD (P = 0.0074), while B07:00/x genotype imposes a significant susceptibility for sporadic Alzheimer's disease (SAD) (P = 0.009). Interestingly, B07:00/x genotype does not show any apparent associations with familial Alzheimer's disease (FAD). Our studies also suggest a pharmacogenetic relationship between drug treatment and presence of a particular genotype in the Iranian LOAD patient population. The Clinical Dementia Rating analysis showed that LOAD patients carrying DRB104:00/x genotype tend to display a downward trend in the disease severity and symptoms after 2-year follow-up with rivastigmine treatment. Moreover, in our total patient population, the carriers of DQB106:00/x and B07:00/x alleles have better and worse responses to rivastigmine respectively. We also measured the clinical relevance of the testing for these genotypes employing prevalence-corrected positive predictive value (PcPPV) formula. The PcPPV of testing for DQB106:00/x in the Iranian LOAD patients was 1.17% which means that people carrying this genotype have half of the probability of the absolute risk for developing LOAD, whereas the PcPPV of testing for B07:00/x was 4.45% for SAD, which can be interpreted as a doubling chance for developing LOAD among the Iranian population carrying this genotype. These results also suggest that DQβ1 peptide containing positively charged AAs histidine and arginine and HLA class I β chain containing negatively charges aspartic acid and glutamic acid in their binding groove plays important roles in protection against and susceptibility for LOAD respectively.