The phosphoinositide 3-kinase (PI3K)/AKT signalling pathway promotes cell proliferation and survival, and is hyperactivated in 70% of human breast cancers. INPP4B is a phosphoinositide 4-phosphatase that degrades PtdIns(3,4)P2 to PtdIns(3)P and inhibits PI3K-dependent AKT signalling. INPP4B has been identified as a tumour suppressor as its expression is lost in basal-like breast cancers, which is associated with poor outcome. Paradoxically increased INPP4B expression has been recently identified in human laryngeal cancer, acute myeloid leukemia (AML), colon cancer and melanoma, and in some contexts mediates therapeutic resistance although the molecular mechanism is unclear. INPP4B overexpression has not been reported in breast cancer. Here we have measured INPP4B mRNA and protein expression in cohorts of primary human breast cancer, and examined the correlation between INPP4B expression, molecular subtype and patient survival. In breast cancer cell lines, INPP4B overexpression increased cell soft agar colony size in a phosphatase-dependent manner, through enhanced cell proliferation. Additionally, overexpression of wild type but not catalytically inactive INPP4B in MCF-10A noncancerous mammary epithelial cells increased cell proliferation in 2D and 3D cultures. Despite this, INPP4B overexpression inhibited AKT activation, suggesting it might promote proliferation through an alternative signalling mechanism. Whole cell proteomic and immunoprecipitation-mass spectrometry analyses have revealed a previously unreported phosphatase-dependent function for INPP4B, which is independent of its role in PtdIns(3,4)P2-mediated AKT signalling. Here, we propose a novel signalling role for INPP4B in regulating breast cancer cell proliferation, which demonstrates the complex and paradoxical role of INPP4B in the regulation of tumourigenesis.