We recently identified NAC-1, member of the bric-a-brac tramtrack broad complex/poxvirus and zinc domain family, as an overexpressed gene in ovarian serous carcinoma and found more frequent NAC-1 protein expression in recurrent compared to primary tumors. In the present study, we assessed the clinical significance of NAC-1 expression in ovarian carcinoma effusions. Formalin-fixed, paraffin-embedded sections from 176 effusions (137 peritoneal, 39 pleural) and 197 corresponding solid tumors (69 primary tumors, 128 solid metastases) were analyzed for NAC-1 expression using immunohistochemistry. Staining intensity and extent results were analyzed for possible association with clinicopathologic parameters and survival. Nuclear NAC-1 immunoreactivity was found in carcinoma cells in 98% of (173/176) effusions, 94% (65/69) of primary tumors, and 95% (121/128) of metastases. Staining intensity and extent were significantly higher in effusions compared with matched solid tumors (P = .002 for intensity, P = .003 for extent compared with primary tumors; P < .001 for both intensity and extent compared with metastases). Furthermore, NAC-1 expression intensity was significantly higher in specimens obtained after the administration of chemotherapy (P = .002) and correlated with shorter progression-free survival (PFS) in analysis of 62 patients with post-chemotherapy effusions (P = .039). International Federation of Gynecology and Obstetrics stage (IV versus III) was the only clinical parameter associated with PFS in this group (P = .004). In Cox analysis, only the International Federation of Gynecology and Obstetrics stage was an independent predictor of shorter PFS (P = .009). In conclusion, NAC-1 expression is higher in ovarian carcinoma cells in effusions compared with their solid tumor counterparts. NAC-1 is up-regulated in tumor cells after chemotherapy, suggesting a role for this protein in tumor progression and in the development of chemotherapy resistance in ovarian cancer.