This systematic review explores the association between HLA-DQB1 genes and scleroderma, a chronic autoimmune disease characterized by collagen synthesis dysregulation and tissue fibrosis. A thorough investigation was conducted by utilizing Google Scholar and PubMed to search for relevant studies in the English language. Two independent reviewers were involved in the process of screening for appropriate studies. A limitation of the exclusion of non-English studies potentially introduces language bias. Inclusion criteria focused on articles investigating the association between HLA genes and scleroderma, providing data on patient and control groups. Risk of bias was conducted using the NIH Quality Assessment Tool for Case-Control Studies. The analyses focused on odds ratios (OR) as a measure of the strength of the association of HLA genes with disease susceptibility. Subgroup analyses were performed for Caucasian and Asian samples, along with a combined analysis. In Caucasian samples, DQB1*02:02 was associated with lower odds of scleroderma (OR=0.51, 95% CI [0.41, 0.63]), while DQB1*03:01 was associated with higher odds (OR=1.55, 95% CI [1.22, 1.97]). In Asian samples, DQB1*04:02 and DQB1*06:01 were associated with higher odds of scleroderma (OR=1.51, 95% CI [1.01, 2.24] and OR=1.33, 95% CI [1.06, 1.67], respectively), while DQB1*06:04 was associated with lower odds (OR=0.55, 95% CI [0.37, 0.82]). Combined samples showed decreased odds of scleroderma in DQB1*06:03 (OR=0.68, 95% CI [0.48, 0.95]) and DQB1*06:04 (OR=0.56, 95% CI [0.39, 0.81]). Future research should explore the interaction between HLA genes and environmental factors to enhance early detection and intervention strategies for individuals at risk of developing scleroderma.