Inositol polyphosphate 4-phosphatase type II (INPP4B) plays a tumor suppressive role by inhibition of phosphatidylinositol 3-kinase (PI3K)/Akt signaling in a variety of tissues. Here we report that, conversely, it functions as an oncogenic regulator in human melanocytic cells through promoting PI3K/SGK3 signaling. While it was commonly upregulated in melanoma cells, knockdown of INPP4B inhibited melanoma cell proliferation in vitro, and retarded melanoma growth in a xenograft model. In contrast, overexpression of INPP4B resulted in increased proliferation and anchorage-independent growth of melanocytes. Strikingly, INPP4B did not impinge on activation of Akt in melanocytic cells. Instead, it promoted PI3K/SGK3 signaling, in that INPP4B knockdown inhibited, whereas overexpression of INPP4B enhanced, activation of SGK3. Indeed, the promoting effect of INPP4B on melanocytic cell proliferation was due to enhanced activation of SGK3, as co-introduction of an active form of SGK3 rescued melanocytes and melanoma cells from inhibition of proliferation triggered by INPP4B knockdown, and knockdown of SGK3 abolished enhancement in cell proliferation resulting from INPP4B overexpression. While activation of SGKs by INPP4B was associated with sustained cellular levels of phosphatidylinositol 3-phosphate, upregulation of INPP4B appeared largely due to downregulation of microRNA-494 (miR-494) and/or miR-599 as a result of gene copy number reduction in melanoma cells. Collectively, these results reveal that INPP4B promotes melanocytic cell proliferation by activation of PI3K/SGK3 signaling, and suggest that the role of INPP4B in the pathogenesis of cancers of different origins needs to be defined discretely.