Studies have suggested that perineural invasion (PNI) and lymphovascular invasion (LVI) serve as independent prognostic factors in colorectal cancer (CRC). Currently, little is known regarding the combination of PNI and LVI as prognostic factors, independent of stage. We hypothesized that this combination was a better prognostic marker than either PNI or LVI alone, and that S100 staining would detect PNI not seen with hematoxylin and eosin (H&E). Surgical pathology slides were retrospectively reviewed for 151 stages I to IV CRC patients who had surgery between January 1, 2008 and December 8, 2008 at 3 Hackensack Meridian Health hospitals in New Jersey. PNI and LVI were detected by H&E staining and a subset of 127 patient samples were additionally examined for PNI by S100 staining. Correlation between staining characteristics and patient outcomes was assessed using the Pearson χ tests and the Fisher exact tests. Survival was analyzed using Kaplan-Meier methods. Of the 151 cases reviewed, 30.5% were positive for PNI and 35.1% were positive for LVI by H&E. The use of S100 staining for PNI enabled its detection in 27 additional cases. Median time from patient diagnosis to death was significantly shorter for patients who were positive for both PNI and LVI (P<0.001). PNI and LVI were individual markers for poor survival in CRC patients and their combined presence had an even worse outcome. Failure to detect PNI on H&E can be overcome by S100 staining.