Background: The aim of the study was to compare acute physiological, biochemical, and perceptual responses during sprint interval exercise (SIE) with breathing through a device increasing added respiratory dead space volume (ARDSV) and without the device. Methods: The study involved 11 healthy, physically active men (mean maximal oxygen uptake: 52.6 ± 8.2 mL∙kg1∙min−1). During four visits to a laboratory with a minimum interval of 72 h, they participated in (1) an incremental test on a cycle ergometer; (2) a familiarization session; (3) and (4) cross-over SIE sessions. SIE consisted of 6 × 10-s all-out bouts with 4-min active recovery. During one of the sessions the participants breathed through a 1200-mL ARDSv (SIEARDS). Results: The work performed was significantly higher by 4.4% during SIEARDS, with no differences in the fatigue index. The mean respiratory ventilation was significantly higher by 13.2%, and the mean oxygen uptake was higher by 31.3% during SIEARDS. Respiratory muscle strength did not change after the two SIE sessions. In SIEARDS, the mean pH turned out significantly lower (7.26 vs. 7.29), and the mean HCO3– concentration was higher by 7.6%. Average La− and rating of perceived exertion (RPE) did not differ between the sessions. Conclusions: Using ARDSV during SIE provokes respiratory acidosis, causes stronger acute physiological responses, and does not increase RPE.