Host genetic factors are known to contribute to disease susceptibility and course in sarcoidosis. They may also be important in defining the pattern of disease presentation and progression, as well as its overall prognosis. We have studied human leukocyte antigen (HLA) class I (n = 31) and class II alleles (n = 56) in a cohort of Indian patients with sarcoidosis and 275 healthy control subjects from north India. Although no specific HLA class I allele association was found among sarcoidosis, the functional classification of HLA-A, -B, and -Cw alleles into supertypes revealed an increased frequency of group 2 ligands (Cw2, Cw4, Cw5) for the Killer cell Ig-like receptors (KIR2DL1) in the patient group as compared with control subjects. Among class II alleles, positive association of DRB1*11, DRB1*14, DQA1*0101/4, and DQB1*0503 alleles with the disease was noticed. Clinical follow-up of the patient cohort up to a 5-yr period showed a predominant occurrence of DRB1*14 and its linked DQ alleles in patients with insidious onset, advanced disease on chest radiographs, and chronic course with frequent relapses on tapering off the prednisolone treatment. Further, multivariate logistic regression analysis revealed that the presence of DRB1*11(odds ratio [OR] 9) and DRB1*14 (OR 7), and absence of DRB1*07 (OR 63 and DQB1*0201(OR 3) alleles, were independent predictors of sarcoidosis. The present findings imply that HLA-associated genetic factors influence the risk for the development of sarcoidosis and disease progression.