Background Laboratory-based biomarkers accurately presenting systemic lupus erythematosus (SLE) disease activity may have a practical value in clinical routine. As shown in many other conditions, complete blood count (CBC)-derived biomarkers may also play a role in SLE. Objectives We aimed to study for the first time the pan-immune-inflammation value (PIV, monocytes x platelets x neutrophils/lymphocytes) and the more established systemic immune-inflammation index (SII, neutrophils x platelets /lymphocytes) in SLE patients and correlate it with serological and clinical findings including disease outcomes. Methods In this retrospective multicentric investigation, we reviewed the clinical records of 148 SLE who had an available CBC at baseline. The latter served for the determination of the neutrophil-to-lymphocyte ratio (NLR), SII, and the PIV. Control groups were studied as well. Univariable as well as multivariable statistics were employed. Results The values for baseline systemic immune-inflammation biomarkers (SIIB) studied were significantly ( p < 0.0001) higher than those observed in healthy controls but comparable to those obtained from patients with other inflammatory conditions. Multivariable analysis revealed that ANA titer > 1:640 remained the only significant ( p < 0.0001) baseline predictor of SLE flare (odds ratio: 7.6, 95% CI 3.1 to 18.8). Improvement of SLE following treatment was associated with the absence of lymphopenia as well as ANA > 1:640 ( p = 0.041). The SLEDAI-2K significantly correlated with NLR, SII, CRP, lymphocytes, and monocytes only on univariable testing. Conclusions Compared to healthy controls the CBC-based SIIB investigated are significantly increased in SLE patients. However, SIIB do not appear to be useful in managing SLE clinically. Nevertheless, we confirm that higher ANA titers can predict flares of SLE.