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It is a common practice to evaluate the reproducibility of fMRI at the group level. However, for clinical applications of fMRI, where the focus is on reproducibility of single individuals, the high test-retest reliability that is sometimes reported for group-based measures can be misleading. On the level of single subjects, reproducibility of fMRI is still far too low for clinical applications, not even meeting the standards to use fMRI for scientific purposes. The goal of this work is to enhance the poor single-subject time course reproducibility of fMRI. For this purpose, we have developed a framework for post-processing fMRI signals using Savitzky-Golay (SG) filters in conjunction with general linear model (GLM) based data cleaning. The parameters of these filters were trained to be the optimal ones based on a dataset of working memory relevant signals. By employing our data-driven filtering framework, we successfully improve the average reproducibility correlation of a single fMRI time course from r = 0.26 (as obtained with a conventional statistical parametric mapping (SPM) data cleaning pipeline) to a fair level of r = 0.41. Additionally, we are able to enhance the average connectivity correlation from r = 0.44 to r = 0.54. Our conclusion is that signal post-processing with a data-driven SG filter framework may substantially improve time course reproducibility compared to conventional denoising pipelines. As a conservative estimate, we conjecture that roughly 10–30% of the population may benefit from optimized fMRI pipelines in a clinical setting depending on the measure of interest while this number was nihil for conventional fMRI pipelines.