The B/plasma cell transcription factor Oct2 and its co-activator Bob1 activate the immunoglobulin heavy chain (IgH) gene enhancer. IgH translocations occur in the majority of myeloma cases, leading to overexpression of genes juxtaposed to the IgH enhancers. We hypothesized that Oct2 and Bob1 are determinants of disease behavior and potential therapeutic targets in myeloma. Oct2 and Bob1 gene expressions were measured in CD138+ plasma cells and CD138-cells from bone marrow samples from patients with myeloma (n = 37); gene expression of Oct2 and Bob1 was higher in CD138+ than in CD138-cells (p < 0.0001). Oct2 and Bob1 protein expressions were assessed in bone marrow tissue microarrays from patients with myeloma (n = 169) with fluorescent immunohistochemistry, and correlated to patient survival. High Oct2 protein expression correlated with reduced survival (hazard ratio [HR] 1.74, 95% confidence interval [CI] 1.11-2.73, p = 0.0164), whereas high Bob1 protein expression correlated with increased survival (HR 0.46, 95% CI 0.29-0.71, p = 0.0008). Oct2 should be explored as a potential selective therapeutic target in myeloma.