| Summary: | Introduction Multimorbidity—the presence of multiple long-term conditions (MLTCs)—is a major global public health issue. Most current healthcare systems are not designed for populations with high multimorbidity prevalence. Little work to date has explored the economic burden and health-related quality of life (HRQoL) impacts of MLTCs over time. Health economic evaluations and longitudinal MLTC studies have been highlighted as key multimorbidity research priorities. Understanding incremental healthcare resource use (HCRU), cost and HRQoL impacts as individuals progress along different multimorbidity trajectories is critical to inform the development of future health systems which are both person-centred and adequately resourced for people with MLTCs. This systematic review will synthesise the available evidence on HCRU, costs and HRQoL impacts of different multimorbidity trajectories.Methods and analysis The review will be reported according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses 2020 statement. A multi-stranded systematic search strategy will be developed to identify studies of multimorbidity trajectories exploring HCRU and costs (direct and indirect) and/or HRQoL over time. Four databases (Embase, MEDLINE, CINAHL, Web of Science) will be searched; limited to peer-reviewed original, English language, longitudinal, quantitative, adult human studies published on/after 2010. A standard data extraction instrument will be applied to included studies following full-text screening by two reviewers. Studies will be quality-assessed using a tool adapted from the Critical Appraisal Skills Programme cohort studies checklist. Data synthesis will use a Synthesis Without Meta-analysis approach. Outcome measures will include HCRU, healthcare costs and HRQoL changes associated with different multimorbidity trajectories.Ethics and dissemination Specific ethics approval has not been sought for this review as it does not directly involve human subjects nor the use of individual-level patient data, and therefore, ethics approval is not required. The review findings will be disseminated via publication in peer-reviewed journal, conference presentations, social media and public engagement events.PROSPERO registration number CRD42024537258.
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