Nicotinamide N-methyltransferase (NNMT) is an S-adenosyl-l-methionine (SAM)-dependent cytosolic enzyme, and a growing body of evidence suggest that it plays an essential role in cancer progression. Recently, NNMT has a role in methylation metabolism and tumorigenesis and was associated with a poor prognosis against numerous cancers. In addition, it has been reported that NNMT has been overexpressed in the stroma of advanced high-grade serous carcinoma and may contribute to decreased survival. This study aimed to identify novel biomarkers to predict resistance and investigate their clinicopathologic significance in paclitaxel-resistant advanced or recurrent ovarian clear cell carcinoma (OCCC). Fluorescence-labeled two-dimensional differential gel electrophoresis (2D-DIGE), immunohistochemical, and MASCOT analyses allowed us to identify the cytoplasmic metabolic enzyme NNMT. In cultured cell studies, NNMT protein expression was higher in paclitaxel-resistant OVMANA and OVTOKO cells than in paclitaxel-sensitive KK and ES-2 cells. Furthermore, although analysis of clinical tissue samples showed no association with poor prognosis in 7 individuals with low NNMT expression in the cytoplasm of OCCC cells, high expression of NNMT in the cytoplasm of OCCC cells may be associated with low sensitivity to paclitaxel in OCCC and may have prognostic implications. Therefore, targeting therapy to reduce cytoplasmic NNMT expression levels may increase the sensitivity of OCCC to paclitaxel.