Background: To date multimorbidity has not received much attention in health policies, even though multiple chronic diseases put high demands on the health care system in industrial nations. Enormous costs of care and a physically, mentally and socially reduced quality of life are common consequences of multimorbidity. Physical activity (PA) has a positive preventive and therapeutic effect on common non-communicable . The objective of this study will be to evaluate the halth benefits and harms of PA interventions for sedentary adults with multimorbidity in primary care settings. Methods: This is the study protocol for a systematic review. We will serach PubMed, MEDLINE (Ovid), Web of Science, CINHAL and the Cochrane Library (from inception onwards). In addition, clinical trial registers and reference lists of included studies will be searched. We will include randomised controlled trials, quasi-experimental and non-randomised trials examining the health benefits and harms of PA interventions with or without additional lifestyle interventions for sedentary adult patients with multimorbidity (e.g. two or more chronic non-communicable diseases) in primary care. Eligible control groups will be standard care, placebo or medications. Two reviewers will independently screen all citations, abstracts data and full text articles. The primary outcomes will be health related quality of life and mortality. Secondary outcomes will include cardiovascular fitness, muscular strength and disease specific outcomes (e.g. depression score), biomarkers as well as control of metabolic risk factors (e.g. blood pressure, HBA1c, body weight) and any adverse event. The study methodological quality will be appraised using appropriate tools. If feasible, we will conduct random effects meta-analysis. Additional analyses will be conducted to explore the potential sources of heterogeneity (e.g. study design, geographical location, or type of intervention). Strength of the body of evidence will be assessed according to the Grading of Recommendations Assessment (GRADE). Discussion: This review will evaluate the evidence on health benefits and harms of PA interventions for sedentary adults with multimorbidity in primary care settings. We anticipate our findings to be of interest to patients, their families, caregivers and healthcare professionals in selecting and conducting optimal health promotion programs. Possible implications for further research will be discussed.