Autologous stem cell transplantation (ASCT) conditioned with melphalan 200 mg/m2 (Mel200) is standard of care for young multiple myeloma (MM) patients. Lower doses of melphalan (MelRed) have been used to reduce toxicity, although data regarding their efficacy are not concordant. We retrospectively evaluated 313 MM patients receiving ASCT at Jena University Hospital between 2003 and 2017. Patients receiving MelRed were on average older (p < 0.001), had a worse renal function (p < 0.001) and more comorbidities (p < 0.001). No differences were seen in treatment response before ASCT between the two groups, whilst after ASCT the rate of at least very good partial responses (VGPR) was significantly higher for patients receiving Mel200 (93% vs. 76%, p < 0.001). PFS (39 vs. 20 months, p < 0.001) and OS (103 vs. 59 months, p = 0.001) were longer with Mel200. Toxicities were comparable in the two groups. After adjusting for age and clinical characteristics using the propensity score, for VGPR before and after ASCT and for double ASCT strategy in a Cox regression analysis, Mel200 was still associated with a lower risk of disease progression (HR = 0.40, 95% CI = 0.40-0.96) and of death (HR = 0.61, 95% CI = 0.35-1.07). Our results confirm that Mel200 is still the standard of care for ASCT eligible myeloma patients.