Background Common variable immunodeficiency (CVID) is a heterogeneous disorder characterized by B-cell dysfunction and, in a subgroup, by expansion of CD21 low B cells. The CD21 low B cells display defects in early B-cell receptor (BCR) signaling resembling those of anergic B cells. Objective We sought to investigate whether B cells from patients with CVID, like anergic B cells, have defects in extracellular signal-regulated kinase (ERK) phosphorylation and in endocytic trafficking of the BCR. Methods Using flow cytometry, we evaluated phosphorylated ERK (pERK) expression and internalization of cross-linked BCR in B-cell subsets. The localization of internalized BCR to lysosome-associated membrane protein 1–positive late endosomes was evaluated with confocal microscopy. Results Constitutive pERK levels were increased in naive and IgM + memory B cells of patients with CVID compared with those of healthy donors, whereas the pERK increment induced by BCR cross-linking was relatively reduced. Intravenous immunoglobulin administration enhanced these anomalies, but they appeared to be intrinsic to B cells from patients with CVID. Cross-linking–induced BCR endocytosis was decreased in the IgM + memory B cells, especially in those with a CD21 low phenotype, but not in the naive B cells of patients with CVID with CD21 low expansion. Internalized BCR localized normally to late endosomes. Pharmacologic inhibition of ERK phosphorylation suppressed BCR endocytosis in B cells of healthy patients and those with CVID. Conclusions The B cells of patients with CVID with CD21 low B-cell expansion resemble anergic B cells based on high constitutive pERK expression. The IgM + memory B cells of these patients, especially those that are CD21 low , have a defect in BCR endocytosis seemingly caused by dysregulated ERK signaling.