Background and Aim Exercise training regimes can lead to improvements in measures of cardiorespiratory fitness (CRF), improved general health, and reduced morbidity and overall mortality risk. High-intensity interval training (HIIT) offers a time-efficient approach to improve CRF in healthy individuals, but the relative benefits of HIIT compared with traditional training methods are unknown in across different disease cohorts. Methods This systematic review and meta-analysis compares CRF gains in randomized controlled trials of short-term (<8 wk) HIIT versus either no exercise control (CON) or moderate continuous training (MCT) within diseased cohorts. Literature searches of the following databases were performed: MEDLINE, EMBASE, CINAHL, AMED, and PubMed (all from inception to December 1, 2017), with further searches of Clinicaltrials.gov and citations via Google Scholar. Primary outcomes were effect on CRF variables: (V) over dotO(2peak) and anaerobic threshold. Results Thirty-nine studies met the inclusion criteria. HIIT resulted in a clinically significant increase in VO2peak compared with CON (mean difference [MD] = 3.32 mLkg(-1)min(-1), 95% confidence interval [CI] = 2.56-2.08). Overall HIIT provided added benefit to (V) over dotO(2peak) over MCT (MD = 0.79 mLkg(-1)min(-1), 95% CI = 0.20-1.39). The benefit of HIIT was most marked in patients with cardiovascular disease when compared with MCT ((V) over dotO(2peak): MD = 1.66 mLkg(-1)min(-1), 95% CI = 0.60-2.73; anaerobic threshold: MD = 1.61 mLkg(-1)min(-1), 95% CI = 0.33-2.90). Conclusions HIIT elicits improvements in objective measures of CRF within 8 wk in diseased cohorts compared with no intervention. When compared with MCT, HIIT imparts statistically significant additional improvements in measures of CRF, with clinically important additional improvements in (V) over dotO(2peak) in cardiovascular patients. Comparative efficacy of HIIT versus MCT combined with an often reduced time commitment may warrant HIIT's promotion as a viable clinical exercise intervention.