HLA-DR4 (DR4) is an HLA-DR serotype that recognizes the DRB1*04 gene products. The DR4 serogroup is large and has a number of moderate frequency alleles spread over large regions of the world.

The serological identification of DR4 is good. The serology of DRB1*04:17 to *04:60 is unknown.

DR4 is associated with extraarticular rheumatoid arthritis, hydralazine-induced female systemic lupus erythematosus, pemphigoid gestationis, pemphigus foliaceus, obstructive hypertrophic cardiomyopathy, IgA nephropathy, 'shared syndrome'-systemic sclerosis/rheumatoid arthritis and polymyalgia rheumatica.

DRB1*04 is associated with increased risk for alopecia areata.

DRB1*04:01 is associated with multiple sclerosis, rheumatoid arthritis, type 1 diabetes, lyme disease induced arthritis. HLA-DRB1*04:01 gene variant is found three times more often in asymptomatic carriers of SARS-CoV-2 than in patients with symptoms of COVID-19. It is known that the prevalence of the HLA-DRB1*04:01 variant directly correlates with the latitude and longitude of the population. This variant of the gene is more common in northern and western Europe, which means that people of European descent are more likely to be asymptomatic carriers that can transmit the disease to more susceptible populations.

DRB1*04:02: drug-triggered/idiopathic pemphigus vulgaris, type 1 diabetes, SLE associated anti-cardiolipin and anti-β₂ glycoprotein I.

DRB1*04:03: polycystic ovary syndrome, SLE associated anti-cardiolipin and anti-β₂ glycoprotein I.

DRB1*04:04: anti-citrullinated fibrinogen in rheumatoid arthritis, autoimmune hepatitis.