Aim: Deprescribing interventions may reduce inappropriate polypharmacy and the associated negative clinical consequences. This systematic review examined current research on the effectiveness of deprescribing interventions implemented within specialist outpatient clinics. Methods: This systematic review was informed by a literature search on 18/10/21 of publications from January 1990 in PubMed and Embase. Studies were included if they focused on patients ≥60 years and measured change in medication burden (defined by number of medications or number of inappropriate medications) as result of an intervention conducted within a specialist outpatient clinic. Methodological quality was assessed by 2 authors using the revised Cochrane risk-of-bias tools. Due to significant heterogeneity between trials, a qualitative synthesis was completed. The primary outcome reviewed was change in medication count or potentially inappropriate medication. Secondary outcomes were maintenance of deprescription and clinical benefits. Results: 19 studies were included for review that included 10,914 participants. They included geriatric outpatient clinics, oncology/haematology clinics, haemodialysis clinics and designated polypharmacy/multimorbidity clinics. Seven RCTs were identified. Other studies included retrospective evaluations and prospective/pilot studies. Four RCTs reported statistically significant reduction of medication burden with intervention, however all studies were assessed as having a high risk of bias. The studies could be grouped into those where the deprescribing intervention was physician-led and implemented, delivered from a multidisciplinary team, or pharmacist-led and physician implemented. Conclusion: The evidence for deprescribing interventions in outpatient clinics is very limited and further research is recommended. The addition of a pharmacist and validated medication assessment tools appear to be enablers.