In the present study the relation between human leukocyte antigen (HLA), optic neuritis (ON) and multiple sclerosis (MS) has been investigated in 56 Iranian patients (46 females and 10 males). HLA‐A and ‐B typing by microlymphocytotoxicity method and HLA‐DRB, DQA and DQB by polymerase chain reaction based on sequence specific primers method was performed for the selected patients with ON. The diagnosis of clinically defined MS (CDMS) was confirmed in 15 of them (26.7%) during their follow‐up. HLA‐A24 was significantly higher in ON patients, whilst A23, A26, and A30 showed a significant decrease in these patients. HLA‐A10 and A26 were absent in CDMS patients and A2 and A11 were significantly decreased in ON and CDMS patients. HLA‐B5, B51, B38, B27, and B35 were significantly increased in ON patients compared with control subjects. HLA‐B44, B16 and B38 alleles were not present in CDMS patients. Regarding DR locus, the frequency of HLA‐DRB1*15 and DRB1*04 has been increased in CDMS patients, whilst the frequency of HLA‐DRB1*07 and *11 was much higher in ON patients. In DQA region, the most frequent allele in the MS patients was DQA1*0102, which was significantly higher than ON patients, and control group. The frequency of DQA1*0103 was significantly increased in both patients group. In DQB1, the frequency of DQB1*0602 increased significantly in the MS patients. In conclusion existence of common genetic basis for early manifestations of MS could be suggested.