We used an unbiased approach of gene expression profiling to determine differential gene expression of all the macromolecular modulators (MMs) considered to be involved in stone formation, in hyperoxaluric rats, with and without treatment with NADPH oxidase inhibitor apocynin. Male rats were fed rat chow or chow supplemented with 5% w/w hydroxy-L-proline (HLP) with or without apocynin-supplemented water. After 28 days, rats were euthanized and their kidneys explanted. Total RNA was isolated and microarray analysis was conducted using the Illumina bead array reader^TM Gene ontology analysis and the pathway analyses of the genes were done using Database for Annotation, Visualization of Integrated Discovery enrichment analysis tool. Quantitative RT-PCR of selected genes was carried out to verify the microarray results. Expression of selected gene products was confirmed using immunohistochemistry. Administration of HLP led to crystal deposition. Apocynin treatment resulted in near complete absence of crystals. Genes encoding for fibronectin, CD 44, fetuin B, osteopontin, and matrix-gla protein, were up-regulated while those encoding for heavy chains of inter-alpha-inhibitor 1, 3 and 4, calgranulin B, prothrombin, and Tamm-Horsfall protein were down-regulated. HLP-fed rats receiving apocynin had a significant reversal in gene expression profiles, those that were up-regulated came down while those that were down-regulated stepped up. Clearly, there are two types of MMs, one is down-regulated while the other up-regulated during hyperoxaluria and crystal deposition. Apparently gene and protein expressions of known macromolecular modulators of CaOx crystallization are likely regulated by ROS produced in part, through the activation of NADPH oxidase.