Background. Reducing the open probability of the ryanodine receptor (RyR) has been proposed to have beneficial effects in heart failure. We investigated whether conditional FKBP12.6 overexpression at the time of myocardial infarction (MI) could improve cardiac remodeling and cell Ca2+ handling. Methods. Wild-type (WT) mice and mice overexpressing FKBP12.6 (Tg) were studied on average 7.5±0.2 weeks after MI and compared to sham for in vivo, myocyte function and remodeling. Results. At baseline, unloaded cell shortening in Tg was not different from WT. [Ca2+]i transient amplitude was similar but SR Ca2+ content was larger in Tg, suggesting reduced fractional release. Spontaneous spark frequency was similar despite the increased SR Ca2+ content, consistent with reduced RyR Po in Tg. After MI, LV dilation and myocyte hypertrophy were present in both groups, but more pronounced in Tg. Cell shortening amplitude was unchanged with MI in WT, but increased in Tg MI. Amplitude of the [Ca2+]i transient was not affected by MI in either genotype, but time to peak was increased; this was most pronounced in Tg. SR Ca2+ content and NCX function were not affected by MI. Spontaneous spark frequency was increased significantly after MI in Tg, and larger than in WT (at 4 Hz: 2.6±0.4 sparks/100μm/s in Tg MI vs. 1.6±0.2 sparks/100μm/s in WT MI, P<0.05). Conclusions. FKPB12.6 overexpression can effectively reduce RyR open probability with maintained cardiomyocyte contraction. However, this approach appears insufficient to prevent and reduce post-MI remodeling indicating that additional pathways may need to be targeted.