To analyse if patients with early relapse after high-dose chemotherapy with stem cell support (HDT) benefit from new treatment strategies in a population-based setting. We conducted a retrospective study of relapse treatment and survival in 348 patients undergoing HDT in Denmark in 1994-2004. Patients were divided into two groups according to time-to-treatment failure (i) within 18 months after HDT and (ii) later than 18 months after HDT. The fraction of patients surviving 3 yr after first relapse was evaluated in relation to calendar periods for introduction of new drugs: before the introduction of thalidomide (1995-1999), before the introduction of bortezomib and lenalidomide (2000-2002) and when patients had access to all treatment modalities (2003-2008). Two hundred and forty-three patients suffered from relapse which required treatment. The median follow-up time was 91.4 months (60-158.8 months) and overall survival was 56.3 months after HDT. The fraction of patients alive 3 yr after first relapse increased in the periods after the year 2000 for patients with late relapse: 1995-1999, 36%; 2000-2002, 57%; and 2003-2008, 72% (P = 0.03), in contrast to patients with early relapse: 1995-1999, 25%; 2000-2002, 33%; and 2003-2008, 31% (P = 0.7). Improved survival was only observed among patients with late relapse after HDT and this may be because of increased use of salvage HDT, improved supportive care and introduction of new drugs.