Innate immunity plays a role in systemic lupus erythematosus (SLE). Our objective was to determine the levels of defensins, which are antimicrobial and immunomodulatory polypeptides, in SLE. Sera from SLE patients and healthy controls were tested for pro‐inflammatory human β‐defensin 2 (hBD‐2) and for α‐defensin human neutrophil peptide 1 (HNP‐1). hBD‐2 could not be detected by enzyme‐linked immunosorbent assay (ELISA) and its mRNA levels were low in SLE patients and similar to those found in controls. In contrast, the mean α‐defensin level in the sera of all SLE patients (11·07 ± 13·92 ng/μl) was significantly higher than that of controls (0·12 ± 0·07 ng/μl). Moreover, 60% of patients demonstrated very high serum levels (18·5 ± 13·36 ng/μl) and 50% showed elevated gene expression in polymorphonuclear cells. High α‐defensin levels correlated with disease activity, but not with neutrophil count. Thus, activation and degranulation of neutrophils led to α‐defensin secretion in SLE patients. Given the immunomodulatory role of α‐defensins, it is possible that their secretion may activate the adaptive immune system leading to a systemic response.