Purpose <p>The aim was to evaluate the safety and possibility of performing high-intensity interval training (HIIT) on a stationary bike for participants with cancer-related lower limb lymphedema (LLL) with and without compression garments in a cross-over design.</p> Methods <p>Twenty-one participants with LLL were randomized to two sessions of HIIT on a stationary bike, one with and one without compression garments. The sessions were separated by a seven-day washout period. The trial was carried out in a hospital setting from September to November 2018.</p> <p>The acceptability and safety of the intervention were assessed. The safety was evaluated as adverse events and immediate and 24-h changes in self-reported symptoms (pain, heaviness, and tension). Additionally, recruitment, completion rate, and post-exercise changes in LLL were assessed by circumferential measurements of the legs, dual energy X-ray absorptiometry (DXA), and bioimpedance spectroscopy (BIS), respectively.</p> Results <p>Twenty-one out of 35 (60%) eligible patients were included, and 19 (90%) patients completed both exercise sessions. Acceptability was high, and there were no adverse events. There was no clinically relevant difference between performing exercise with and without compression in self-reported symptoms or in limb volume. Small statistically significant differences in soft tissue mass (164.2&#xa0;g corresponding to 1.4%) and extracellular fluid (L-Dex range &lt; 5 units) were observed with and without compression, respectively, both favoring exercise with compression.</p> Conclusion <p>HIIT on a stationary bike was acceptable for patients with LLL and seemed safe regardless of the use of compression garments.</p> Trial registration <p>Clinicaltrials.gov registration (NCT03653819).</p>