Human leukocyte antigen class II typing, using polymerase chain reaction-sequence-specific primers, was performed in 52 Black South Africans with systemic sclerosis (SSc) and 112 controls. Increased frequencies of DR2 in the overall SSc group (OR = 2.4), DRB1*0301 in the limited cutaneous SSc (lcSSc) subset (OR = 9.0), and DQB1*0301/4 in the diffuse cutaneous SSc (dcSSc) subset (OR = 9.0) were observed. Pulmonary fibrosis was associated with DRB1*11 and anti-topoisomerase I antibodies were associated with DPB1*1301 and DRB1*15. Patients with anti-fibrillarin antibodies (AFAs) had increased the frequencies of DRB1*1101 allele group (OR = 16) and DQB1*0603/14 (OR = 13.6). These findings provide new serological and immunogenetic data on a previously unreported population. The association of AFAs with class II alleles merits further investigation.