CD28 expression and serum levels are significantly increased in patients with SLE than in healthy controls (HC). Until now, there are no studies of proximal promoter polymorphisms of CD28 gene in SLE. Therefore, our objective was to investigate the polymorphisms present in the proximal promoter of CD28 in a group of SLE and HC and to associate the polymorphisms present with the CD28 serum levels of 40 patients and 40 controls. One hundred and seven patients as well as 108 controls matched by age range and genders were included. The 11 ACR criteria were analyzed on the clinical files, and the proximal promoter region of CD28 gene was analyzed by direct sequencing of a 489-basepair fragment. C28 serum levels (sCD28) were measured by ELISA technique in 40 patients and 40 controls. Only two of the eight reported polymorphisms were found, and they correspond to rs35593994 (-372 A/G) and rs56156157 (-145 -/C). The first had a prevalence of 41 and 36% in patients and controls respectively and the second of 1.4% in both groups. None of these polymorphisms were associated with SLE, and the polymorphism -372 A/G was not associated with the clinical features of disease. Likewise, the association with the sCD28 and the genotypes of -372 A/G polymorphism was not significant. The polymorphisms of the proximal promoter of CD28 are not associated with SLE, and the polymorphism -372 A/G is not associated with the diagnostic criteria of SLE or the sCD28.