Background <p>Compliance with training protocol is essential to achieve physiologic improvements associated with exercise. This study aimed to assess the compliance and response to a 4-week high-intensity interval training (HIIT)-based protocol as part of a multimodal prehabilitation program for patients with colorectal cancer awaiting surgery and to explore potential associated factors.</p> Methods <p>The study analyzed 136 patients allocated to a prehabilitation exercise training program in a multicenter prehabilitation program. Compliance with training was defined based on intensity and time in HIIT during each session. Response to training was considered if patients increased peak oxygen uptake (VO_2peak) ≥10 % or &gt;2.5&#xa0;ml/kg/min after training.</p> Results <p>Data compliance was available for 104 patients. Non-compliant participants (<i>n</i> = 37, 35.6 %) had lower cardiorespiratory fitness (CRF) at baseline (mean difference, –2.74 ml/kg/min; <i>p</i> &lt; 0.01) and tended to be older (<i>p</i> = 0.053). Approximately one of four patients exhibited a clinically meaningful response to exercise. Younger patients and those with lower CRF at baseline had greater odds of responding to training (Epx[B], 0.739; 95 % confidence interval {CI}, 0.58–0.93]) and Exp(B), 476 [95 % CI, 0.266–0.85 respectively). Furthermore, patients who increased VO_2peak at least 2.5&#xa0;Mml/kg/min had no severe complications (Comprehensive Complication Index [CCI], ≤20) and experienced better postoperative recovery than the non-responding patients (<i>p</i> = 0.043 and <i>p</i> &lt; 0.001 respectively).</p> Conclusions <p>Compliance with a HIIT protocol among colorectal cancer patients was found to be affected by baseline CRF and age. Only one of four patients showed a clinically significant improvement in VO_2peak after training, which was associated with less severe postoperative complications.</p>