Amifostine (WR-2721; Ethyol) is a well-known cytoprotector, but a possible role in preventing extrahaematological toxicity after high-dose therapy (HDT) has never been investigated. We compared two historical groups of patients who either received (group A, n = 35) or did not receive (group B, n = 33) amifostine (740 mg/m2) before high-dose (HD) melphalan, followed by autologous infusion of peripheral blood progenitor cells (PBPCs). Amifostine was well tolerated at this dose level. Emesis grade 1-2 was the most important side-effect, but the interruption of infusion was never required. The incidence and median duration of severe mucositis (grade 3-4) was 21% and 0 d (range 0-11 d) in group A and 53% and 7 d (range 0-11 d) in group B. The duration of analgesic therapy was also significantly lower in group A (0 d; range 0-12) than in group B (6 d, range 0-20) (P = 0.0001). Severe diarrhoea (3% vs. 25%; P = 0.01) and emesis (9% vs. 34%; P = 0.01) were also reduced in group A in comparison with group B. No differences were observed between the two groups for haematological recovery. This retrospective study strongly suggests that amifostine can reduce severe mucositis and the use of analgesic drugs in this setting. A randomized study is warranted to confirm these preliminary results.