Levels of C-reactive protein (CRP) have been shown to rise in acute illnesses such as infections and some autoimmune diseases, but not in flares of systemic lupus erythematosus (SLE). Our goal was to investigate the high-sensitivity CRP (hsCRP) response to infection versus disease flare in patients with SLE, and to compare this with the erythrocyte sedimentation rate (ESR) response in these patients. We aimed to determine the hsCRP level that distinguishes between infection and flare in SLE, and investigated the correlation between hsCRP and organ involvement in SLE. We reviewed electronic medical records of all patients with SLE admitted to Cedars Sinai Medical Center between 28 August 2001 and 27 April 2008. Patients were divided into three groups based on the reason for hospitalization: (1) lupus flare; (2) active infection; and (3) both lupus flare and active infection. Data were collected on patient demographics, medication use, microbial culture results, organ involvement in lupus flare, ESR and CRP levels. Data were collected on 85 eligible patients, of whom 54 had a lupus flare, 22 had active infection and eight had both. While the ESR levels did not differ significantly between patients with disease flare and active infection, the hsCRP level was significantly lower in the lupus flare group than in the infection group. Most patients in the lupus flare group who had a significantly high hsCRP level had serositis. We found that at a cut-off of above 5 mg/dl, hsCRP level was correlated with infection with a specificity of 80%. At a cut-off of above 6 mg/dl, hsCRP correlated with infection with a specificity of 84%. hsCRP level was found to be significantly higher in patients with pulmonary involvement than without. hsCRP levels are significantly lower in SLE patients with disease flare than in those with active infection. Elevated hsCRP levels can be used as a predictor of active infection in SLE patients with a high specificity. We review the relationship between IL-6 and hsCRP production in lupus patients.