HGTD‐P is a hypoxia‐responsive pro‐apoptotic protein that transmits hypoxic signals directly to mitochondria. When overexpressed, HGTD‐P induces cell death via typical mitochondrial apoptotic cascades. However, much is unknown about post‐transcriptional modification and signaling networks of HGTD‐P in association with cell death‐regulating proteins. We performed yeast two‐hybrid screening to identify the molecules involved in HGTD‐P‐mediated cell death pathways. In this study, we show that heat shock protein 90 physically interacts with HGTD‐P and that suppression of Hsp90 activity by low concentrations of geldanamycin reduced HGTD‐P‐induced mitochondrial catastrophe through inhibition of mitochondrial translocation of HGTD‐P.