The Sarco(endo)plasmic reticulum Ca²⁺-ATPase2 (SERCA2) is down regulated in cardiac hypertrophy with decompensation. We sought to determine if mice heterozygous (HZ) for the SERCA2 allele would develop greater bladder hypertrophy and decompensation than their WT littermates following partial bladder outlet obstruction (pBOO). We found that following 4 weeks of surgically created pBOO, SERCA2 HZ murine bladders showed significantly less hypertrophy, improved in vitro cystometry perfomance, diminished expression of the slow myosin isoform A analyzed by RT-PCR, a significant drop in nuclear translocation of Nuclear Factor of Activated T Cells (NFAT) by EMSA, and decreased cell proliferation within the fibroblasts of the smooth muscle layer following BrdU labeling when compared to their WT littermates. Thus, in contrast to cardiac muscle, deletion of a SERCA2 allele confers protection against bladder hypertrophy in a murine model of pBOO. Compensatory mechanisms in HZ mice seem to be related to the calcineurin pathway. Further studies are underway to better define the molecular basis of this observation, which has potential clinical applications.