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Summary: Cell volume regulation is a vital system for cellular activities. When perturbed by hypoosmotic or hyperosmotic stress, cells immediately induce the cell volume recovery system, regulatory volume decrease (RVD) or regulatory volume increase (RVI), respectively. In contrast to the knowledge about effector molecules, the molecular mechanisms linking osmosensing to RVD/RVI induction remain unknown. Additionally, few reciprocal responders in the bidirectional osmotic stress response have been identified. We previously reported that ASK3 bidirectionally switches its kinase activity under osmotic stress. Herein we demonstrate that ASK3 controls both RVD and RVI under osmotic stress. Using a high-content genome-wide small interfering RNA (siRNA) screen, we identify PP6 as a direct ASK3 inactivator. Furthermore, PP6 rapidly interacts with ASK3 in an osmolality-dependent manner, and it inactivates ASK3 to induce RVI and, thereby, cell survival under hyperosmotic stress. These findings suggest that the PP6-ASK3 interaction is a core module in the bidirectional osmotic stress response. : Osmotic stress comprises two types of information: intensity and directionality. Nevertheless, few bidirectional cellular systems have been identified. Using a high-content genome-wide siRNA screen, Watanabe et al. unveil that a PP6-ASK3 module bidirectionally interprets and converts osmotic stress signals to control cell volume homeostasis. Keywords: apoptosis signal-regulating kinase 3, ASK3, protein phosphatase 6, PP6, high-content genome-wide siRNA screen, osmotic stress, cell volume regulation