Background: Community-based exercise rehabilitation programmes for chronic disease are an effective alternative to traditional hospital-based programmes. MedEx Wellness is a novel community-based exercise rehabilitation programme that integrates a range of chronic diseases. The aim of this trial was to investigate the effect of participating in MedEx Wellness on physical, clinical and psychological health. Methods/design: A prospective cohort study was conducted. Participants were recruited at induction to the MedEx Wellness programme following referral from healthcare professionals. Participants underwent a baseline assessment before commencing the exercise programme and repeat assessments at 3, 6 and 12 months. The primary outcome was cardiorespiratory fitness (6 minute time trial) at 12 months. Secondary outcomes included health-related quality of life (EuroQoL-5D, Satisfaction with Life Scale, Warwick Edinburgh Mental Wellbeing Scale, Patient Health Questionnaire 8, Functional Assessment of Cancer Therapy (FACT) Questionnaire), free living activity behavior (accelerometer) and healthcare utilization (recall questionnaire). Tertiary outcomes included blood pressure (24 h), biomarkers (lipids, glucose and C-reactive protein), other components of physical fitness, including strength (handgrip test, sit-to-stand test); flexibility (sit-and-reach test); body composition (body mass index and waist-to-hip ratio), and falls risk (timed up and go test); cognitive function, including attention (Attention Network Task), memory (Luck & Vogel Visual Working Memory Task) and cognitive reserve. Exploratory outcomes included psychosocial determinants of physical activity (self-efficacy, social support, intentions). 3 Discussion: This trial will evaluate whether participation in the MedEx Wellness programme has positive effects on physical, clinical and psychological health in men and women with a range of chronic diseases Trial Registration: ISRCTN Registry ISRCTN10351412.