Doxorubicin-based chemotherapy is used in the treatment of sarcomas. Toxic side effects and poor response rates underline the demand for an improvement in current chemotherapeutic protocols. Recently, it has been reported that parvoviruses confer various antineoplastic properties to infected cells, and that adeno-associated virus type 2 (AAV-2) infection sensitizes malignant epithelial cells to radiation- or chemotherapy-based genotoxic treatment. Thus, we analyzed whether AAV-2 infection leads to an improved efficacy of doxorubicin chemotherapy in malignant mesenchymal cells, using 13 human sarcoma cell lines. Therapeutic effects were analyzed by measuring cell viability and proliferation (WST-1, colony forming, and propidium iodide assays). Additionally, permissivity for AAV-2 infection was determined by Southern dot blot analysis. AAV-2 infection strongly increased the efficacy of doxorubicin treatment in rhabdomyo-, fibro-, osteo- and chondrosarcoma cells in a dose-dependent manner. This effect was not observed in liposarcoma and synovial sarcoma cells, although a susceptability to AAV-2 infection was documented. Our results indicate that the sensitization effects towards genotoxic treatment exerted by non-pathogenic AAV-2 infection are not restricted to epithelial malignancies but may also be exploited for the improvement of chemotherapy in patients suffering from rhabdomyo-, fibro-, osteo-, or chondrosarcomas.