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Although polypharmacy is associated with significant morbidity, deprescribing can be challenging. In particular, clinicians express difficulty with their ability to deprescribe (i.e. reduce or stop medications that are potentially inappropriate). Evidence-based deprescribing guidelines are designed to help clinicians take action on reducing or stopping medications that may be causing more harm than benefit.Determine if implementation of evidence-based guidelines increases self-efficacy for deprescribing proton pump inhibitor (PPI), benzodiazepine receptor agonist (BZRA) and antipsychotic (AP) drug classes.A deprescribing self-efficacy survey was developed and administered to physicians, nurse practitioners and pharmacists at 3 long-term care (LTC) and 3 Family Health Teams in Ottawa, Canada at baseline and approximately 6 months after sequential implementation of each guideline. For each drug class, overall and domain-specific self-efficacy mean scores were calculated. The effects of implementation of each guideline on self-efficacy were tested by estimating the difference in scores using paired t-test. A linear mixed-effects model was used to investigate change over time and over practice sites.Of eligible clinicians, 25, 21, 18 and 13 completed the first, second, third and fourth survey respectively. Paired t-tests compared 14 participants for PPI and BZRA, and 9 for AP. Overall self-efficacy score increased for AP only (95% confidence intervals (CI) 0.32 to 19.79). Scores for domain 2 (develop a plan to deprescribe) increased for PPI (95% CI 0.52 to 24.12) and AP guidelines (95% CI 2.46 to 18.11); scores for domain 3 (implement the plan for deprescribing) increased for the PPI guideline (95% CI 0.55 to 14.24). Longitudinal analysis showed an increase in non-class specific scores, with a more profound effect for clinicians in LTC where guidelines were routinely used.Implementation of evidence-based deprescribing guidelines appears to increase clinicians’ self-efficacy in developing and implementing a deprescribing plan for specific drug classes.Prescribers have identified many challenges in their ability to carry out deprescribing activities.Self-efficacy reflects how long one will persevere when faced with challenges.Using evidence-based deprescribing guidelines influences self-efficacy for deprescribing.A self-efficacy assessment tool provides a novel approach to evaluating usefulness of polypharmacy management initiatives.