Consolidation therapy has improved the outcome of newly diagnosed PCNSL patients. Whole-brain radiotherapy (WBRT) was the first consolidation strategy used and represented the gold standard for many years, but at the expense of a high risk of neurotoxicity. Thus, alternative strategies are being investigated in order to improve disease outcomes and to spare the neurocognitive side effects due to WBRT.We reviewed published studies on PCNSL patients treated with HDC/ASCT, focusing on the efficacy and safety of the conditioning regimens. Prospective and retrospective studies, published in the English language from 1992 to 2022, in high-quality international journals were identified in PubMed.Consolidation with HDC containing highly CNS-penetrating agents (thiotepa, busulfan or BCNU) followed by ASCT provided long-term disease control and survival in PCNSL patients. Two prospective randomized studies, comparing HDC/ASCT versus WBRT, reported similar progression-free survival (PFS) and similar results on the decline in neurocognitive functions in a substantial proportion of patients after WBRT but not after HDC-ASCT. A recent randomized study comparing HDC/ASCT versus non-myeloablative consolidation reported a longer PFS in transplanted patients.ASCT conditioned with regimens, including highly CNS-penetrating agents, represents, to date, the best choice among the available consolidation strategies for fit newly diagnosed PCNSL patients.