CO₂ gas generating poly(lactic-co-glycolic acid) (PLGA) microsphere (MS) was designed for rapid release of tanespimycin (17-AAG) in transarterial chemoembolization (TACE) treatment of hepatocellular carcinoma (HCC). As poorly water-soluble drug is generally released from PLGA MS in a sustained manner, the drug release profile should be controlled according to its clinical indications. In current study, responding to immediate increase in hypoxia inducible factor-1α (HIF-1α) level under hypoxia state followed by embolization of tumor feeding arteries, sodium bicarbonate (NaHCO₃) was added to PLGA/17-AAG MS for fast drug release by CO₂ gas generation in slightly acidic tumor microenvironment. With the aid of NaHCO₃, initial burst release of 17-AAG was available without losing the micron-size and spherical shape of designed MS for embolization of artery. Acid-responsive CO₂ gas generation and subsequent immediate release of 17-AAG from MS were successfully verified. PLGA/17-AAG/NaHCO₃ MS-treated group exhibited higher antiproliferation and apoptosis induction efficacies in McA-RH7777 and SNU-761 cells. McA-RH7777 tumor-implanted rats treated by TACE using PLGA/17-AAG/NaHCO₃ MS presented a complete therapeutic response. All these findings suggest that developed tumor microenvironment-responsive gas-generating MS can be efficiently applied to TACE therapy of HCC.