Sarcoidosis is a multisystemic disorder of unknown etiology, affecting primarily the lung and characterized by epithelioid granulomas. Disease association studies showed human leukocyte antigen (HLA) class II to be related to sarcoidosis. Initially, we studied the association of sarcoidosis with DQB1, and in the present study, we evaluated all amino acid variants of the HLA-DPB1, -DQB1, -DRB1, -DRB3, -DRB4 and -DRB5 genes to identify possible polymorphisms associated with the disease. Patients and controls were typed for class II genes to the allele level by sequence-based typing. Multiple logistic regression models showed DRAla71 and DQPhe9 to be independently associated with the disease. Subdivision of patients according to their radiographic stage resulted in identification of DRArg74 as independent associated residue in the RS I group, whereas DRAla71 and DQTyr30 were associated with RS II-IV groups. Polymorphic residues specifically associated with sarcoidosis shed new light on the characteristics of sarcoidosis-triggered peptides. Overall, pocket 9 of DQ and pocket 4 of DR seem to be the most important areas involved in the association with sarcoidosis.