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Background People living with HIV (PLHIV) present impaired muscle metaboreflex, which may lead to exercise intolerance and increased cardiovascular risk. The muscle metaboreflex adaptations to exercise training in these patients are unknown. The present study aims to investigate the effects of a supervised multimodal exercise training on hemodynamic and autonomic responses to muscle metaboreflex activation in PLHIV. Methods and design In this randomized clinical trial protocol, 42 PLHIV aged 30–50 years will be randomly assigned at a ratio of 1:1 into an intervention or a control group. The intervention group will perform exercise training (3x/week during 12 weeks) and the control group will remain physically inactive. A reference group composed of 21 HIV-uninfected individuals will be included. Primary outcomes will be blood pressure and heart rate variability indices assessed during resting, mental stress, and activation of muscle metaboreflex by a digital sphygmomanometer and a heart rate monitor; respectively. Mental stress will be induced by the Stroop Color-Word test and muscle metaboreflex will be activated through a post-exercise circulatory arrest (PECA) protocol, being the latter performed without and with the application of a capsaicin-based analgesic balm in the exercised limb. Secondary outcomes will be heart rate, peripheral vascular resistance, stroke volume, cardiac output, blood lactate, anthropometric markers and handgrip maximal voluntary contraction. The intervention and control groups of PLHIV will be evaluated at baseline and after the intervention, while the HIV-uninfected reference group only at baseline. Discussion The findings of the present study may help to elucidate the muscle metaboreflex adaptations to exercise training in PLHIV. Trial registration This study will be performed at University of Rio de Janeiro State following registration at ClinicalTrials.gov as NCT04512456 on August 13, 2020.