Congenital disorder of glycosylation Ia (CDG-Ia) is an autosomal recessive disease, characterized by the impaired biosynthesis of the N-linked oligosaccharide chains of proteins due to a deficiency of phosphomannomutase (PMM), the enzyme converting mannose-6-phosphate into mannose-1-phosphate. We investigated the consequences of the altered N-linked glycoprotein (GP) biosynthesis on the quantity and quality of glycosphingolipids (GSLs) in fibroblasts of CDG-Ia patients. First, we found that CDG-Ia fibroblasts contain an increased amount of total GSLs when compared with normal fibroblasts. Further, we assessed by metabolic labeling of CDG-Ia fibroblasts with radioactive sugar precursors, including galactose and N-acetylmannosamine, that a diminished biosynthesis of cellular GPs is antagonized by an increased biosynthesis of GSLs. An increased GSL biosynthesis was also observed by means of radiolabeled lipid precursors including sphingosine and lactosylceramide. Notably, also the degradation of GLSs is slowed down in CDG-Ia fibroblasts. Finally, when we labeled normal human fibroblasts and CHO cells with radioactive galactose in the presence and absence of deoxymannojirimycin (dMM), an inhibitor of N-glycan processing, we found that this cellular model mimics what occurs in CDG-Ia fibroblasts. Since an inverse relationship between GP expression and GSL content does exist, we assume that increased glycosphingolipid biosynthesis is secondary to protein hypoglycosylation. Altogether, our data suggest that the cell metabolic machinery may be able to partially re-equilibrate protein hypoglycosylation with increased biosynthesis of glycosphingolipids, possibly to preserve the overall physico-chemical equilibrium of the outer layer of the plasma membrane. Glycoproteins (GPs) and glycosphingolipids (GSLs) represent two major classes of glycoconjugates present in mammalian cells. The glycosylation of both classes of molecules shares some common features. Noteworthy, 1) the subcellular distribution of GP and GSL glycosylating enzymes is similar, with the Golgi apparatus being the compartment where the majority of glycosylations occurs (1-3); 2) some of the enzymes which glycosylate proteins and lipids are the same, e.g. those responsible for blood group antigenicity (4, 5); 3) the precursor pool of nucleotide-sugars of both GP and GSL glycosylation within the Golgi lumen is indistinguishable (6); 4) the GP and GSL transport through the Golgi complex displays biochemical and kinetical similarities (7); 5) a relevant portion of neosynthesized GPs and the totality of GSLs are delivered from the Golgi to the plasma membrane, the final site