It was recently shown that the CD24 Ala57Val (rs 52812045) polymorphism plays a significant role in susceptibility to systemic lupus erythematosus (SLE) in a Spanish population, which has not been confirmed in other ethnic groups. We investigated the distribution of the CD24 Ala57Val polymorphism in patients with SLE (n = 250) and controls (n = 350) in Poland. The odds ratio (OR) for patients with SLE with the Ala/Val genotype compared with Ala/Ala genotype was 1.490 [95% confidence interval (CI) = 1.052-2.111, P = 0.0275], and OR for the Val/Val genotype compared with Ala/Ala genotypes was 2.001 (95% CI = 1.154-3.467, P = 0.0154). Moreover, we observed a significant association between the CD24 Val allele and the presence of anti-Scl-70 antibody (Ab) OR = 2.155 (1.438-3.229, P = 0.0002). There was also an association of Val allele with the presence of anti-snRNP Ab OR = 1.984 (1.266-3.110, P = 0.0034) in patients with SLE. We also found that the CD24 Val/Val and Ala/Val genotypes contribute to immunologic manifestations OR = 2.244 (1.323-3.806, P = 0.0037). Our observations indicate that the CD24 Ala57Val polymorphism may predispose to SLE incidence and can be linked to immunologic manifestations and production of autoantibodies in this disease.