Monocytes and macrophages are equipped with Toll-like receptors (TLRs) and cytokine receptors for sensing cues in their microenvironments, to which they respond by differentiating into either pro-inflammatory, classically-activated (M1 polarized) killer macrophages or inflammation-resolving, alternatively-activated (M2 polarized) repair macrophages. Macrophage polarization is a key determinant of inflammation in homeostasis and disease. In patients with cystic fibrosis (CF), M1 macrophages constantly activated by recurrent infection are coupled with defective M2 polarization, resulting in exaggerated pulmonary inflammation. Recently, phosphatidylinositol 3-kinase gamma (PI3Kg) has emerged as a key molecular switch in M1 macrophages, biasing them towards M2 outputs to suppress inflammation. The role of PI3Kg in M2 macrophages is not well understood and its potential role in CF macrophages has not been investigated. In this study we assessed the roles of PI3Kg and the cystic fibrosis transmembrane conductance regulator (CFTR) in regulating macrophage polarization. Our data demonstrate that both PI3Kg and CFTR in macrophages contribute to constraining inflammation during M1 polarization and promoting inflammation-resolving M2 polarization. Healthy macrophages with pharmacologically inhibited CFTR and macrophages from patients with CF both show higher pro-inflammatory responses and reduced anti-inflammatory responses. Anti-inflammatory Akt signaling is also defective in these macrophages. Macropinosomes in macrophages, besides being a nonselective endocytic pathway for extracellular fluid uptake, also serve as a platform for PI3K/Akt signaling during macrophage activation. In CF, defective CFTR causes reduced macropinocytosis resulting in lower Akt signaling and dysregulated anti-inflammatory responses in both M1 and M2 macrophages. PI3Kg and CFTR are thus shown to modulate inflammatory responses at multiple levels that can contribute to non-resolving inflammation in CF.