The cardiovascular response induced by resistance exercise with blood flow restriction (BFR) seems to be lower or comparable to traditional exercise in healthy individuals. However, the potential for BFR to be used for at risk populations highlights a need to further attenuate the cardiovascular response, potentially via the modality of exercise. PURPOSE: To compare the cardiovascular response to unilateral (UN), bilateral (BI), and alternating (AL) BFR exercise. METHODS: 13 males and 7 females performed four sets (30 seconds rest) of UN, BI, and AL knee-extensions to failure with 30% one-repetition maximum and 40% arterial occlusion pressure. Pulse wave analysis was measured before and after exercise. Data, presented as mean (SD), were analyzed using Bayesian RMANOVA. RESULTS: AL caused greater changes in: aortic systolic [ΔmmHg: AL=21 (8); UN=13 (10); BI=15 (7); BF10=29.63], diastolic [ΔmmHg: AL=13 (8); UN=7 (10); BI=8 (7); BF10=5.13], and mean arterial [ΔmmHg: AL=19 (8); UN=11 (10); BI=13 (7); BF10=48.39] blood pressures. Brachial [ΔmmHg*bpm: AL=4945 (2340); UN=3218 (1412); BI=3461 (1430); BF10=31.74] and aortic [ΔmmHg*bpm: AL=6134 (2479); UN=4200 (1722); BI=4525 (1664); BF10=114.83] rate pressure product as well as heart rate [Δbpm: AL=26 (14); UN=18 (8); BI=19 (11); BF10=5.82] were also greatest with AL. Augmentation pressure [ΔmmHg: UN=-3 (5); BI=-2 (6); AL=-1 (6); BF10=0.19], pulse pressure [ΔmmHg: UN=6 (6); BI=7 (7); AL=8 (5); BF10=0.27], augmentation index [Δ%: UN=-6 (12); BI=-7 (11); AL=-6 (16); BF10=0.16], wave reflection magnitude [Δ%: UN=-5 (8); BI=-5 (7); AL=-4 (7); BF10=0.15], forward wave height [ΔmmHg: UN=8 (6); BI=8 (6); AL=8 (4); BF10=0.15], and reflected wave height [ΔmmHg: UN=1 (3); BI=2 (4); AL=3 (3); BF10=0.31] were not different between conditions. Exercise volume was greater in AL [kg: AL=1835 (1725); UN=915 (312); BI=893 (313); BF10=29.17]. Ratings of perceived exertion (BF10=3.99e+144) and discomfort (BF10=2.0e+73) increased with sets. AL had an elevated discomfort (BF10=5548.97). CONCLUSION: The greater cardiovascular response following alternating BFR exercise in healthy individuals, suggests those at risk of a cardiovascular event should choose unilateral or bilateral BFR exercise until further work determines the degree to which this modality can be tolerated.