Abstract Background The clinical outcomes following rituximab (RTX) treatment in patients with SLE is highly variable. We aimed to identify predictive and prognostic factors associated with RTX therapy outcomes in patients with SLE. Methods Studies in adults and paediatric patients with SLE were included. We included randomized clinical trials (RCTs) for predictors of differential treatment effect and cohort studies for potential prognostic factors in patients treated with RTX (global clinical, cutaneous and renal either response or relapse and side effects). Methodological quality was assessed using Cochrane Collaboration Risk of Bias tool and the Quality In Prognosis Studies Tool (QUIPS) for RCTs and cohort studies, respectively. The quality of subgroup analyses testing predictors of differential treatment response was also evaluated. A best evidence synthesis was performed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework. Results Sixteen articles were included (3 from 2 RCTs and 13 from 6 cohort studies). The overall quality of evidence (QoE) was low to very low (GRADE framework). QoE for predictive factors based on RCTs analysing sociodemographic variables, was rated very low due lack interaction tests, limited power of subgroup analyses, study limitations and imprecisions. Disease-related factors including clinical phenotype and severity, baseline anti-ENA antibodies and anti-Ro antibodies, interleukin (IL) 2/21 single nucleotide polymorphism (SNP), as well as post-RTX complete B cell depletion and earlier B cell repopulation showed some evidence for prognostic value, but were rated low to very low QoE because of early phase of investigation (exploratory analysis), insufficient adjustment for confounding in most studies, high risk of bias, inconsistency and imprecisions. Conclusions To date studies addressing prognostic factors are hypothesis generating and cannot be used to make any specific recommendations for routine clinical practice. A number of potential predictors/prognostic factors were identified which require to be validated as being specific for response to RTX therapy and to enable more personalised use of this agent.