Background: Various studies have assessed the effectiveness of clinical pathways (CPs) in inpatient settings and provided systematic evidence that they positively affect patient outcomes and efficiency of care, thus lowering costs. In recent years, CP implementation is often combined or extended with clinical pathway software (CPS). Until now, no systematic literature review appears to exist which synthesizes the evidence on the effectiveness of CPS in inpatient settings, in relation to the CPs they support. Objectives: The purpose of this study was to systematically review evidence on (perceived) effectiveness of clinical pathway software (CPS) and investigate mechanisms explaining the effects of CPS implementation on outcomes. Methods: We searched MEDLINE via PubMed and Scopus, for English-language original articles. Articles were included if they examined the effectiveness and/or the perceived effectiveness of CPS in the inpatient setting. They were analyzed for evidence on structure, process and outcome effects, as well as for mechanisms explaining such effects in relation to contextual factors. Results: From 2904 articles, 12 studies met our inclusion criteria. The seven studies reporting on adherence provide conclusive evidence that CPSs can improve adherence. We also found conclusive evidence of improvement of process related measures regarding appropriate diagnostics, timeliness of care, and length of stay (LOS). Evidence on costs and outcomes is weak and/or less conclusive. This holds true both for patient outcomes (e.g. mortality/patient satisfaction) and caregiver outcomes (e.g. user satisfaction). The studies presented no direct evidence on mechanisms explaining how CPS relate to process and outcome improvements. Conclusions: The primary effects of CPS to increase adherence may in turn positively impact other process indicators such as LOS, timeliness of care, and diagnostic effectiveness. Subsequent effects on costs, outcomes for patients, physicians and nurses remain inconclusive and call for further research. Further research should explicitly take context into account. The scarce and weak evidence-base relating CPS implementation to process and outcome effects needs development along the same lines.