Aim: We examined whether HLA-DRB1*1501 and four VDR SNPs influence the macrophage response to infection with Mycobacterium tuberculosis (Mtb) via innate immune versus drug treatment or drug delivery mechanisms. Materials & methods: Monocyte-derived macrophages from 24 healthy donors were infected with Mtb in vitro . Survival of intracellular bacilli and secretion of cytokines and nitric oxide by the infected cells were monitored with and without exposure to isoniazid and rifabutin. Results: Haplotype analysis was conducted, and an arbitrary score of genetic ‘susceptibility’ (S ) score ranging from -3 to +3 was assigned to donors based on the presence or absence of genetic markers. S scores correlated more strongly with Mtb survival (r = 0.68) than TNF and nitric oxide (NO; r = ∼0.01–0.11). A specific haplotype was significantly associated with decreased Mtb survival (p < 0.05), increased NO and decreased IL-10/IL-4. Macrophages with S scores ≥ 2 secreted significantly (p < 0.05) more IL-10 and IL-4, and less NO upon infection, and supported Mtb survival. Microparticulate drugs showed higher bactericidal activity than free drugs, irrespective of S score. Conclusion:S score predicts colonization of macrophages by Mtb, as does haplotype analysis. Drug-containing microparticles are superior to free drugs across diverse genetic backgrounds. Original submitted 12 June 2012; Revision submitted 4 January 2013