Objcetive To assess the efficacy and safety of lenalidomide plus dexamethasone (LD) compared with placebo plus dexamethasone (PD) for relapsed or refractory multiple myeloma. Methods Data were searched in The Cochrane Library (Issue 3, 2010), MEDLINE (with PubMed, 1966 to Nov. 2010), EMbase (1984 to Nov. 2010), CBMdisc (1978 to Nov. 2010), and CNKI (1979 to Nov. 2010), and also searched in clinical trials register for ongoing studies and completed studies with unpublished data. The references of the included studies and relevant supplement or conference abstracts were handsearched. Randomized controlled trials were included. The data were extracted, and then the quality of the included studies was assessed by two reviewers independently. RevMan 5.0 software was used for meta-analyses for studies with low heterogeneity. Results Two studies involving 704 participants were included. One was high quality study, while the other was unclear about randomization and allocation concealment. The adverse outcomes of LD, such as mortality (RR=0.78, 95%CI 0.62 to 0.97, P=0.03) and incidence of disease progression (RR=0.16, 95%CI 0.08 to 0.34, Plt;0.000 01), were better than those of PD, which had significant differences. The overall response rate was higher in the LD group than in the PD group (RR=2.75, 95%CI 2.22 to 3.41, Plt;0.000 01). The incidence of thrombotic event (RR=3.20, 95%CI 1.78 to 5.73, Plt;0.000 1), the Grade Three and Grade Four neutropenia (RR=10.20, 95%CI 5.76 to 18.08, Plt;0.000 01), the Grade Three and Grade Four thrombocytopenia (RR=2.08, 95%CI 1.28 to 3.38, P=0.003), and the incidence of drug withdrawal or dosage reduction due to adverse reactions (RR=1.34, 95%CI 1.21 to 1.49, Plt;0.000 01) were all higher in the LD group than in the PD group. Conclusion The efficacy of LD is superior to that of PD for relapsed or refractory multiple myeloma, but the incidence of drug adverse events, such as thrombosis, Grade Three or Grader Four neutropenia or thrombocytopenia, is also higher than that of PD, which has to be prevented positively.