Background: Individuals with severe mental illness experience increased morbidity and mortality compared to the general population. Adverse effects of antipsychotics, including weight gain, may contribute to the development of metabolic syndrome (MetS), which is associated with increased risks of all-cause and cardiovascular disease mortality. We aim to provide a comprehensive overview of clinical, biochemical and genetic factors associated with MetS among patients with schizophrenia spectrum disorders using second-generation antipsychotics (SGA).Methods: A literature search was performed in Pubmed and Embase to identify all cohort studies, cross-sectional studies and clinical trials investigating associations with MetS in patients with schizophrenia spectrum disorders using SGAs. We extracted and enumerated clinical, biochemical and genetic factors reported to be associated with MetS. We defined factors associated with MetS as factors being reported as associated with MetS in two or more studies.Results: 58 studies were included in this review (n = 12,123). In total, 62 factors were found to be associated with increased risk of MetS. Thirty one out of 58 studies investigated factors that were reported as associated with MetS in two or more studies. With regard to clinical factors, we found gender, higher age, concomitant use of mood stabilizers, higher baseline and current BMI, earlier SGA exposure, higher dose, longer duration of treatment, psychosis and tobacco smoking to be significantly associated with MetS. Furthermore, the biochemical factors hypo-adiponectinemia, elevated levels of C-reactive protein (CRP) and higher white blood cell (WBC) count were identified as factors associated with MetS. Among pharmacogenetic factors, the rs1414334 C-allele of the HTR2C-gene was associated with MetS in patients using SGA.Conclusion: In this systematic review investigating clinical, biochemical and genetic factors associated with MetS in patients using SGAs we found that higher age, higher baseline BMI, higher current BMI and male as well as female gender were positively associated with MetS across all antipsychotics. This study may set the stage for the application of clinical, biochemical and genetic factors to predict the risk of developing MetS in patients using SGAs. Future research is needed to determine which patients using SGAs are at risk to develop MetS in clinical practice.