Objective: Among individuals experiencing chronic homelessness, there is a high rate of co-occurring mental health and substance use, which has traditionally been addressed through the delivery of permanent supportive housing along with substance use and mental health services. However, this population often has difficulty engaging in treatment for co-occurring disorders, which can result in exacerbation of symptoms and housing loss. Maintaining Independence and Sobriety Through Systems Integration, Outreach, and Networking (MISSION) is a co-occurring mental health and substance use wraparound approach that was pilot-tested alongside Permanent Supportive Housing (PSH) to improve treatment access and engagement. This pilot was part of a state plan to end homelessness in the Boston metro area. Methods: This open pilot study enrolled 136 individuals who were chronically homeless and offered one year of MISSION along with PSH. Program participants also received baseline and 6- and 12-month follow-up assessments. Results: At one-year follow-up, 82.4% of the program participants were housed in PSH. However, due to limited affordable housing in the Boston metro area, it took on average 6.20 months to house the program participants. Furthermore, while MISSION was feasible to implement alongside PSH, fidelity to the MISSION model was lower than expected. This pilot also examined the role of housing status on clinical outcomes and found that the program participants who were housed at the time of discharge displayed a statistically significant improvement in emergency room visits for mental health complaints, the Psychosis subscale of the Behavior and Symptom Identification Scale (BASIS-32), illegal drug use, and pharmacotherapy treatment. Conclusions: This pilot study demonstrated that systematically integrating PSH and MISSION can improve access and engagement in care, housing retention, and mental health outcomes. Despite the preliminary success and while taking into account the limitations of the open single-group pre/post design, this study also identified the lack of affordable housing as a potential barrier to placement as well as the critical role of housing for improved clinical outcomes. Randomized controlled trials are needed to test MISSION with PSH as well as perhaps PSH with and without MISSION to tease apart the effects of integrating both approaches simultaneously.