Myocardial infarction elicits nerve sprouting. However, the time course and spatial distribution of nerve sprouting and its relationship to neurotrophic factor expression is unclear. We created myocardial infarction in FVB mice by ligating the left coronary artery. Hearts were removed at 3 hrs to 13 months after MI for growth associated protein 43 (GAP-43) immunostaining. The nerve density (mm2/mm2) was determined by ImagePro software. In another group of mice, myocardial tissues were processed and analyzed using Affymetrix RG U74V2 array. Results show that the density of nerve fibers immunopositive for GAP-43 was the highest 3 hours after myocardial infarction in both the peri-infarct area and in the remote area. The outer loop of the ventricle has higher nerve density than in inner loop of the ventricle. The differences were at its peak 3 hours after MI, but persist for 2 months afterwards. The expression of nerve growth factor, Insulin-like growth factor, leukemia inhibitory factor, transforming growth factor-b3 and interleukin-1a was increased up to 2 months after myocardial infarction as compared to normal control. qRT PCR analyses showed increased mRNA for tyrosine hydroxylase, synaptophysin, nerve growth factor and leukemia inhibiting factor in the peri-infarct area up to 2 months after MI but to roughly 3 days in the remote area. We conclude that myocardial infarction results in immediate upregulation of nerve growth factor, Insulin-like growth factor, leukemia inhibitory factor, transforming growth factor-b3 and interleukin-1a in the peri-infarct area and to a less extent in the remote area. These changes persisted for at least two months, and were associated with increased nerve sprouting activity which was most active in the outer loop of the heart.