A recent report has indicated that cadmium‐induced testicular damage in CF‐1 mice can be prevented by pretreatment with calmodulin inhibitors such as chhrpromazine (CPZ), trifluoperazine, or N‐(6‐aminohexyl)‐5‐chloro‐1‐naphthalene sulfonamide (W‐7). However, the basis of this tolerance to cadmium is unclear and has not been demonstrated in any species other than mice. Thus, we examined the effects of the calmodulin inhibitor CPZ on cadmium toxicity in male Wistar (WF/NCr) rats. A single sc injection of 25 μmol CdCI2/kg proved nonlethal over 24 h but caused the typical spectrum of testicular lesions and increases in hemoglobin content (as assessed by hemoglobin absorbance in testicular supernatant). Pretreatment with 40 μmo/ CPZ/kg had no effect on cadmium‐induced testicular lesions but did reduce testicular hemoglobin content, while 120 μmot CPZ/kg moderately reduced the severity of testicular lesions and hemoglobin contenls. CPZ pretreatment in some cases increased cadmium content in liver and reduced testicular content but had no effect on renal levels. Cadmium treatment markedly increased hepatic and renal metal‐lothionein (Ml), a metal‐binding protein often associated with tolerance to cadmium. CPZ alone likewise increased hepatic Ml and Ml mRNA, but did not modify renal Ml, renal Ml mRNA, or testicular Ml mRNA. In contrast to liver and kidney, testicular cadmium‐binding protein (TCBP) decreased in rats exposed only to cadmium or to CPZ, while CPZ pretreatment had no further effect on cadmium‐induced reductions in TCBP levels. These results indicate that, like mice, CPZ in rats can reduce the testicular toxicity of cadmium as indicated by CPZ‐'mduced reductions in testicular vascular lesions and hemoglobin contents. However, in rats CPZ has a less dramatic effect on such cadmium‐induced lesions than in mice. The CPZ‐induced stimulation of hepatic Ml gene expression or modification of toxicokinetics may both play roles in this acquired tolerance to cadmium.