Multiple sclerosis (MS) is a clinically heterogeneous demylinating disease and an important cause of acquired neurologic disability. MS has been reported from different regions of India and its infrequency has been attributed to have genetic implications. Further, a high incidence of MS and its human leukocyte antigen B12 (HLA-B12) associations have been reported among highly inbred Parsi population from Mumbai. However, consistent HLA associations have not been reported from India. We analyzed the HLA-B, -Cw, and -DRB1 allele associations among 23 clinically definite Western Indian non-Parsi MS patients and compared them with 146 ethnically matched clinically normal individuals. HLA serologic (A, B, and Cw) as well as molecular (DRB1) typing methodology was followed. The study revealed a significant increase of HLA-A11 (24% vs. 13%; OR = 2.6; EF = 0.14; 95%CI = 1.1-3.05), B16 (4.3% vs 0.3%; OR = 13.8; EF = 0.03; 95% CI = 1.19-134.44), Cw7 (15.2% vs 3.7%; OR = 5.46; EF = 0.12; 95% CI = 0.944-17.86), and DRB1*15 (21.7% vs 2.2%; OR = 16.15; EF = 0.19; 95% CI = 1.33-68.64). Further molecular subtyping of HLA-DRB1*15 among the patients revealed two novel alleles, DRB1*1506 (20%) and DRB1*1508 (30%), along with the commonly reported DRB1*1501 (50%) for the first time in MS patients that were hitherto unidentified from other parts of India and world as well. This study reveals that there is a complexity of the genetic susceptibility to MS in different populations studied and reported.