Article summary Article focus An evaluation of the cost-effectiveness of Housing First in comparison to treatment as usual for homeless adults with mental illness in five Canadian cities with a 2-year follow-up. Primary outcomes include housing stability, quality of life and social functioning. The correlates of different trajectories and the critical ingredients of the intervention for sub-populations will also be investigated. Key messages The first and largest multi-site trial of this complex housing and support intervention will provide information about implementation and outcomes. The addition of site specific intervention arms to a core common protocol will allow investigation of innovative adaptations that are tailored to local context. The inclusion of a broader homeless population receiving a less intensive service model will increase the policy relevance of findings. Strengths and limitations of this study A larger sample size (n=2500) and a wider range of outcome variables than in previous trials are strengths of this study. This study utilises a concomitant mixed methods process evaluation that includes fidelity assessments. Variation in sample characteristics and in treatment as usual across five cities may limit opportunities for aggregate analyses.