Objective To evaluate the clinical values of complement C3 and C4 and C-reactive protein (CRP) in the differential diagnosis of disease relapse and infection in systemic lupus erythematosus (SLE). Methods Sixty-three hospitalized SLE patients during 2011-2014 were retrospectively analyzed in this study. Patients were grouped according to the presence of infection and SLE disease activity index (SLEDAI). The laboratory findings, including CRP, erythrocyte sedimentation rate(ESR), complement and immunoglobulin were compared between the infected group (n=20) and non-infected group (n=43) and the flare group (n=44) and inactive group (n=19). Correlation analysis was also made between SLEDAI and serum markers. Results The levels of CRP, ESR, IgA, and SLEDAI in the infection group were significantly higher than those of the non-infection group (P<0.05). The levels of ESR and IgG in the flare group were significantly higher and C3 was significantly lower than those in the inactive group (P<0.05). Correlation analysis found that C3 was negatively correlated with SLEDAI (r=-0.666, P<0.01), but CRP was not correlated with C4(r=0.073, r=0.143; P>0.05). Conclusion CRP is elevated when SLE patients have infection, but C3 and C4 have no decrease or only with slight decrease. During flare of SLE patients, C3 is decreased and C4 has no obvious decrease, with CRP not elevated or slightly elevated. It is indicated that C3 and CRP are valuable in the differential diagnosis of disease relapse and infection in SLE.