Stigma toward mental health and substance use problems (MHSUP) represents a global public health challenge that undermines the quality of mental health care. This study looked at whether an anti-stigma intervention would result in a significant decrease in stigmatizing and discriminatory attitudes among Community Health Center (CHC) staff toward individuals with MHSUP, as well as clients’ experiences of MHSUP stigma with CHC staff. A study in 6 CHCs in Toronto employed a cluster-randomized trial to determine the efficacy of an anti-stigma intervention toward people with MHSUP by CHC staff. Participants included 395 staff and 90 clients across 4 waves of the study. The study employed mixed effect models to test for differences between intervention sites and control sites over time. Mixed effects regressions show significantly better improvements in stigma scales among staff in the experimental sites, suggesting the intervention was successful in improving attitudes among CHC staff toward people with MHSUP. Three of the 6 interactions for staff and 2 of 4 interactions among clients indicated that the interventions beneficially affected stigma. The quantitative data with clients was not strong in finding a reduction in stigma. This tested innovative intervention may contribute to the development of effective anti-stigma initiatives for MHSUP in primary care worldwide.