The objective of this study was to evaluate inducible nitric oxide synthase (iNOS) and nuclear factor-kappaB inhibitor (NF-kappaB) expression and the potential chemoprotective effects of an NF-kappaB inhibitor, pyrrolidine dithiocarbamate (PDTC), against cisplatin-induced testicular damage in rats. Rats were divided into 4 equal groups: group 1, control; group 2, injected with cisplatin (CIS) for 5 days (7 mg/kg/day intraperitoneally [IP]); group 3, injected with PDTC alone; group 4, injected with CIS plus PDTC (100 mg/kg IP). Body and testicular weights, plasma testosterone levels, and histopathologic structure of the testicular tissue were determined. The iNOS and NF-kappaB activity were evaluated immunohistochemically by staining p65 to define NF-kappaB activity. Malondialdehyde (MDA), reduced glutathione (GSH), and nitric oxide (NO) levels and glutathione peroxidase (GSH-Px) activity were assessed in testicular tissue. Body and testicular weights, plasma testosterone levels, activity of GSH-Px, and GSH levels were all significantly decreased, whereas the levels of MDA and NO were significantly increased in rats of the CIS group. PDTC treatment increased plasma testosterone levels. A significant increase in GSH levels and GSH-Px activity and a decrease in MDA and NO levels in testicular tissue were observed in the CIS + PDTC group. Immunohistochemically, there was a marked staining for iNOS and NF-kappaB/p65 expression in rats injected with CIS compared with the control (P < .001). CIS caused irregular seminiferous tubules, reduction of seminiferous epithelial layers, significant arrest of maturation, and perivascular fibrosis. Moreover, PDTC administration to CIS-treated rats significantly prevented these histopathologic chances, as well. CIS induces iNOS expression through activation of NF-kappaB/p65, and CIS-induced testicular toxicity may be prevented by PDTC, which is a selective NF-kappaB inhibitor.