BackgroundThe objective of this study is to analyze the influence of a 14-week periodized circuit training protocol on patients with knee osteoarthritis (OA), in randomized intervention groups, on thigh intermuscular adipose tissue (interMAT), body composition, systemic inflammation, cartilage degradation, and its repercussion on pain, functional performance and quality of life.MethodsThis study presents a protocol for a randomized controlled trial. Sixty selected participants diagnosed with knee OA grades II and III, 40–65 years old and BMI < 30 kg/m2, will be randomly divided into three groups:periodized circuit training, strength training, and educational protocol. The circuit training and strength training protocols consist of 14-week training protocols conducted 3 times a week. The circuit training group will perform selected exercises previously stratified as light, moderate, and intense, arranged progressively in a circuit model, the strength group will perform regular strength exercises, and the educational protocol group will participate in a 14-week protocol with lectures twice a month about healthy lifestyles. Baseline and follow-up evaluations will be conducted for thigh interMAT (computed tomography), body composition (DXA), inflammation (IL-1β, IL-6, IL-10, TNF-α, leptin, and adiponectin), and joint degradation biomarkers (uCTX-II and sCOMP), performance-based tests (30s Chair Stand Test, 40 m Fast-paced Walk Test and Stair Climb Test), quadriceps and hamstring maximal isometric voluntary contraction (MIVC), and questionnaires (WOMAC and pain catastrophizing scale). Repeated measures ANOVA will be used to compare differences between groups (circuit training X strength training X educational protocol) at the different times of assessment (baseline x follow-up or baseline x during protocol x follow-up) for each of the dependent variables. When significant main effects were found, the pots hoc Bonferroni test will be used to identify statistical differences. A significance level of 5% (p < 0.05) will be adopted.DiscussionThis will be the first randomized controlled trial to assess the effects of a circuit training protocol on patients with knee OA on thigh intermuscular adipose tissue (interMAT). Given the prevalence and impact of OA and the widespread availability of this intervention, assessing the efficacy of a low-cost, non-pharmacological, and non-invasive treatment for knee OA patients has the potential for immediate and high clinical impact.Trial registrationClinicalTrials.gov, NCT02761590, registered in May 4, 2016.Electronic supplementary materialThe online version of this article (10.1186/s12891-018-2325-y) contains supplementary material, which is available to authorized users.