HIV infection leads to severe B cell dysfunction, which manifests as impaired humoral immune response to infection and vaccinations and is not completely reversed by otherwise effective antiretroviral therapy (ART). Despite its inability to correct HIV-induced B cell dysfunction, ART has led to significantly increased lifespans in people living with HIV/AIDS. This has in turn led to escalating prevalence of non-AIDS complications in aging HIV-infected individuals, including malignancies, cardiovascular disease, bone disease, and other end-organ damage. These complications, typically associated with aging, are a significant cause of morbidity and mortality and occur significantly earlier in HIV-infected individuals. Understanding the pathophysiology of these comorbidities and delineating clinical management strategies and potential cures is gaining in importance. Bone loss and osteoporosis, which lead to increase in fragility fracture prevalence, have in recent years emerged as important non-AIDS comorbidities in patients with chronic HIV infection. Interestingly, ART exacerbates bone loss, particularly within the first couple of years following initiation. The mechanisms underlying HIV-induced bone loss are multifactorial and complicated by the fact that HIV infection is linked to multiple risk factors for osteoporosis and fracture, but a very interesting role for B cells in HIV-induced bone loss has recently emerged. Although best known for their important antibody-producing capabilities, B cells also produce two cytokines critical for bone metabolism: the key osteoclastogenic cytokine receptor activator of NF-κB ligand (RANKL) and its physiological inhibitor osteoprotegerin (OPG). Dysregulated B cell production of OPG and RANKL was shown to be a major contributor to increased bone loss and fracture risk in animal models and HIV-infected humans. This review will summarize our current knowledge of the role of the OPG/RANK–RANKL pathway in B cells in health and disease, and the contribution of B cells to HIV-induced bone loss. Data from mouse studies indicate that RANKL and OPG may also play a role in B cell function and the implications of these findings for human B cell biology, as well as therapeutic strategies targeting the OPG/RANK–RANKL pathway, will be discussed.