Frequent emergency department (ED) users experiencing homelessness are associated with high costs for healthcare systems yet interventions for this group have been minimally investigated. This study used 24-month data from a multisite randomized controlled trial of Housing First (HF) to examine how effective the intervention is in helping frequent ED users with a mental illness to achieve housing stability, improve behavioural health and functioning, and reduce their ED use. Findings showed that HF is effective in stably housing frequent ED users despite their complex health needs. Reductions in ED use and substance use problems, and improvements in mental health symptoms and community functioning were found for frequent ED users in both the HF and treatment as usual conditions.