As an integral component of the microenvironment in colorectal cancer (CRC), stromal cells can influence tumor progression. Found in the extracellular matrix of CRC, secreted protein acidic and rich in cysteine (SPARC) is expressed in stromal and CRC cells. While SPARC's influence on CRC is not clear, we hypothesized that epigenetically regulated SPARC expression in the microenvironment stromal cells of CRC can affect primary CRC progression and is influenced by lymphovascular invasion (LVI). Quantitative immunohistochemistry (IHC) analysis of paraffin-embedded (n=72) from 37 LVI-positive and 35 LVI-negative primary CRCs was performed. MassARRAY sequencing was performed to assess the methylation status of the promoter region in 22 LVI-positive and 20 LVI-negative CRC and to identify specific CpG island(s) regulating SPARC expression. SPARC in CRC cells was not correlated with LVI, whereas SPARC in the microenvironment stromal cells was inversely related to LVI (P < 0.0001). There was a direct relationship between LVI and 6 specific CpG site methylation in the SPARC promoter region of stromal cells (P = 0.017) but not in CRC cells. Stromal SPARC expression inversely correlated with VEGF-A expression in CRC (P = 0.003) and positively correlated with HSP27 expression (P = 0.009). The results suggested that the epigenetic regulation of SPARC expression in tumor cells versus stromal cells of CRC is significantly different. Stromal cell SPARC expression is epigenetically influenced by LVI of CRC tumors, and may play a significant role in primary CRC progression.