Background People with serious mental illness (SMI) often suffer high healthcare costs and enduring loss of quality of life. Increasing our understanding of the cost-effectiveness of people with SMI is important when striving for optimal health at affordable costs. AIM To describe aspects that can be important for cost-effectiveness research targeting people with SMI. Method These aspects are demonstrated by considering pro-active care, rehabilitation and involuntary treatment Results The possible involvement of a large number of stakeholders outside of healthcare requires cost-effectiveness research to also map the costs and benefits outside of healthcare, preferably for each stakeholder specifically. Availability of data, the possibility to combine datasets, and ways to deal with dropouts require extra attention. Conclusion Cost-effectiveness research targeting people with SMI could be enhanced when solutions are found for the availability of data inside and outside of healthcare and when dropout can be compensated for by other sources of data, such that costs and benefits for each stakeholder can be estimated more reliably.