Introduction: Osteoarthritis (OA) is one of the most prevalent chronic conditions among older adults, with the medial tibiofemoral joint being most frequently affected. The knee adduction moment is recognized as a surrogate measure of the medial tibiofemoral compartment joint load and therefore represents a validintervention target. This article provides the rationale and methodology for THE LO study (Train High, Eat Low for Osteoarthritis), which is a randomized controlled trial that is investigating the effects of a unique, targeted lifestyle intervention in overweight/obese adults with symptomatic medial knee OA. Research question: Compared to a control group given only lifestyle advice, do the effects of the following interventions result in significant reductions in the knee adduction moment: (1) gaitretraining; and (2) combined intervention (which involves a combination of three interventions: (a) gait retraining, (b) highintensity progressive resistance training, and (c) high-protein/lowglycaemic-index energy-restricted diet)? It is hypothesized that the combined intervention group will be superior to the isolated interventions of the high-protein/low-glycaemic-index diet group and the progressive resistance training group. Finally, it is hypothesized that the combined intervention will result in a greater range of improvements in secondary outcomes, including: muscle strength, functional status, body composition, metabolic profile, and psychological wellbeing, compared to any of the isolated interventions or control group. Design: Single-blinded, randomized controlled trial adhering to the CONSORT guidelines on conduct and reporting of non-pharmacological clinical trials. Participants: One hundred and twenty-five community-dwelling people are being recruited. Inclusion criteria include: medial knee OA, low physical activity levels, no current resistance training, body mass index ≥ 25 kg/m2 and age ≥ 40 years Intervention and control:The participants are stratified by sex and body mass index, and randomized into one of five groups: (1) gait retraining; (2) progressive resistance training; (3) high-protein/low-glycaemic-index energy-restricted diet (25 to 30% of energy from protein, 45% of energy from carbohydrates, <30% of energy from fat, and glycaemic index diet value <50); (4) a combination of these three active interventions; or (5) a lifestyle-advice control group. All participants receive weekly telephone checks for health status, adverse events and optimisation of compliance. Measurements: Outcomes aremeasured at baseline, 6 and 12months. The primary outcome is the peak knee adduction moment during the early stance phase of gait. The secondary outcome measures are both structural (radiological), with longitudinal reduction in medial minimal joint space width at 12 months, and clinical, including: change in body mass index; joint pain, stiffness and function; body composition; muscle strength; physical performance/mobility; nutritional intake; habitual physical activity and sedentary behaviour; sleep quality; psychological wellbeing and quality of life. Discussion: THE LO study will provide the first direct comparison of the long-term bene?ts of gait retraining, progressive resistance training and a high-protein/low-glycaemic-index energy-restricted diet, separately and in combination, on joint load, radiographic progression, symptoms, and associated co-morbidities in overweight/obese adults with OA of the knee.