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Marrow cells from patients with higher-risk myelodysplastic syndrome ( MDS) exhibit constitutive nuclear factor ( NF)-κB activation. The proteasome inhibitor, bortezomib, has limited efficacy as a single agent in acute myeloid leukaemia. Its activity on leukaemic cell lines is potentiated by chemotherapy. We treated 43 higher-risk MDS patients with bortezomib (1·5 mg/m2, days 1, 4, 8 and 11) and low dose cytarabine arabinoside ( LDAC; 10 mg/m2, then 20 mg/m2 from days 1-14), every 28 d for four cycles. Median follow-up was 29·7 months. Responses were seen in 12 of the 43 patients (28%), including complete response ( CR, n = 1), marrow- CR ( n = 3), partial response ( PR, n = 5) and haematological improvement ( HI, n = 3). Responses were seen in 12 (36%) of the 33 previously untreated patients (11% CR, 13% PR, 2·5% HI), compared to none in the 12 previously treated patients ( P < 0·01). Responders had better overall survival (median 18·2 vs. 10 months). One CR and 3 marrow- CRs were seen in patients with complex karyotypes. Main toxicity was haematological, responsible for infection in six patients and bleeding in 3. Three patients with Grade 1-2 pre-treatment haematotoxicity developed Grade 3-4 toxicity. Neuropathy was seen in 12% of patients. The addition of bortezomib to LDAC in higher-risk MDS may improve results obtained with LDAC alone, especially in patients with unfavourable karyotypes. [ABSTRACT FROM AUTHOR]