Zmpste24 is a metalloproteinase required for the processing of prelamin A to lamin A, a structural component of the nuclear lamina. Zmpste24 deficiency results in the accumulation of prelamin A within cells, a complete loss of mature lamin A, and misshapen nuclear envelopes. Zmpste24-deficient (Zmpste24^–/–) mice exhibit retarded growth, alopecia, micrognathia, dental abnormalities, osteolytic lesions in bones, and osteoporosis, which are phenotypes shared with Hutchinson–Gilford progeria syndrome, a human disease caused by the synthesis of a mutant prelamin A that cannot undergo processing to lamin A. Zmpste24^–/– mice also develop muscle weakness. We hypothesized that prelamin A might be toxic and that its accumulation in Zmpste24^–/– mice is responsible for all of the disease phenotypes. We further hypothesized that Zmpste24^–/– mice with half-normal levels of prelamin A (Zmpste24^–/– mice with one Lmna knockout allele) would be subjected to less toxicity and be protected from disease. Thus, we bred and analyzed Zmpste24^–/–Lmna^+/– mice. As expected, prelamin A levels in Zmpste24^–/–Lmna^+/– cells were significantly reduced. Zmpste24^–/–Lmna^+/– mice were entirely normal, lacking all disease phenotypes, and misshapen nuclei were less frequent in Zmpste24^–/–Lmna^+/– cells than in Zmpste24^–/– cells. These data suggest that prelamin A is toxic and that reducing its levels by as little as 50% provides striking protection from disease.