The current unblinded, randomized controlled trial analyzed psychiatric symptoms, substance use, and life skills outcomes in participants after 21 months in the Housing First (HF) program. The HF group (intervention) comprised 46 participants and the treatment-as-usual (TAU) group (control) comprised 41 participants. Quantitative outcome measures were collected at baseline and 8 and 21 months. Primary outcomes were mental health and substance use. Secondary outcomes were everyday life skills. Descriptive and comparative analyses and linear regression models are presented. At 21 months, the HF group presented significantly better outcomes regarding alcohol and cannabis use than the TAU group. Moreover, the subgroup of HF participants with severe mental illness had significant improvements in psychotic symptoms, anxiety, depression, social relations, and cannabis use compared to TAU participants. [Journal of Psychosocial Nursing and Mental Health Services, 60(9), 46-55.].