Cadmium is a potent nephrotoxin that has been shown to induce apoptosis in some cells, but also to prevent it under certain circumstances. In several clinical situations and experimental models of injury to the renal glomerulus, pathological proliferation of mesangial cells is followed by resolution involving mesangial cell apoptosis. We investigated the effects of Cd²⁺ on rat mesangial cells induced to undergo apoptosis through either the extrinsic receptor-mediated pathway or the intrinsic mitochondrial-dependent pathway. Camptothecin initiated the intrinsic pathway with activation of caspase-9, and caspase-dependent cleavage of procaspase-3. Tumor necrosis factor (TNF-) initiated caspase-8 activity and cleavage of procaspase-3 at the convergence point of the two pathways. However, procaspase-8 levels were low, and caspase-9 was also activated in response to TNF-, characteristic of what have been termed type II cells. With both TNF- and camptothecin, concurrent exposure to 10 µM CdCl₂ suppressed DNA laddering, nuclear condensation, and procaspase-3 cleavage. It also decreased activity of both caspase-8 and caspase-9, prevented caspase-8-dependent cleavage of the pro-apoptotic factor, Bid, and suppressed release of cytochrome c from mitochondria. At this 10 µM concentration, Cd²⁺ was unique among a number of metal ions in preventing DNA fragmentation. We conclude that Cd²⁺ is anti-apoptotic in rat mesangial cells, acting by a mechanism that may involve general caspase inhibition. This may have consequences for the resolution of nephritis in situations of mesangial cell hyperproliferation.