Diurnal or circadian rhythms are fundamentally important for healthy cardiovascular physiology, and play a role in timing of onset and tolerance to myocardial infarction (MI) in patients. Whether time of day of MI triggers different molecular and cellular responses that can influence myocardial remodelling is not known. This study was designed to test whether time of day of MI triggers different gene expression, humoral, and innate inflammatory responses that contribute to cardiac repair after MI. Mice were infarcted by left anterior descending coronary artery ligation (MI model) within a 2 hour time window either shortly after lights on or lights off, and the early remodelling responses at 8 hours post infarction were examined. We found that sleep-MI preferentially triggers early expression of genes associated with inflammatory responses, whereas wake-MI triggers more genes associated with metabolic pathways and transcription/translation, by microarray analyses. Homozygous clock mutant mice exhibit altered diurnal gene expression profiles, consistent with their cycling prior to onset of MI. In the first 8 hours, crucial for innate immune responses to MI, there are also significant differences in sleep-MI and wake-MI serum cytokine responses and in neutrophil infiltration to infarcted myocardium. By 1 week post-MI there are differences in survivorship between the sleep and wake MI mice that could be explained by the different molecular and cellular responses. Our whole-body physiology, tissues and cells exhibit endogenous daily rhythms and understanding their role in triggering effective responses after MI could lead to new strategies to benefit patients with cardiovascular disease.