This investigation assessed the efficacy of sprint interval training (SIT) combined with postexercise blood-flow restriction as a novel approach to enhance maximal aerobic physiology and performance. In study 1, a between-groups design was used to determine whether 4 weeks (2 days per week) of SIT (repeated 30 s maximal sprint cycling) combined with postexercise blood-flow restriction (BFR) enhanced maximal oxygen uptake (V̇(O2max)) and 15 km cycling time-trial performance (15 km TT) compared with SIT alone (CON) in trained individuals. The V̇(O2max) increased after BFR by 4.5% (P = 0.01) but was unchanged after CON. There was no difference in 15 km TT performance after CON or BFR. In study 2, using a repeated-measures design, participants performed an acute bout of either BFR or CON. Muscle biopsies were taken before and after exercise to examine the activation of signalling pathways regulating angiogenesis and mitochondrial biogenesis. Phosphorylation of p38MAPK(Thr180/Tyr182) increased by a similar extent after CON and BFR. There was no difference in the magnitude of increase in PGC-1α, VEGF and VEGFR-2 mRNA expression between protocols; however, HIF-1α mRNA expression increased (P = 0.04) at 3 h only after BFR. We have demonstrated the potency of combining BFR with SIT in increasing V̇(O2max) in trained individuals, but this did not translate to an enhanced exercise performance. Sprint interval training alone did not induce any observable adaptation. Although the mechanisms are not fully understood, we present preliminary evidence that BFR leads to enhanced HIF-1α-mediated cell signalling.