Patterns of invasion and stromal response are understudied in vulvar squamous cell carcinoma (vSCC). The aim of this study was to explore whether histologic features such as an infiltrative pattern of invasion and fibromyxoid stromal response (FMX-SR) are meaningful prognostic factors. We reviewed 143 vSCC resections and correlated patterns of invasion and stromal response with patient age, ethnicity, depth of invasion (DOI), tumor size, perineural invasion (PNI) (S100/AE1/3 stain), lymph node involvement (LNI), extranodal extension, margin status, pathologic stage, and recurrence. Univariate analyses of continuous variables were performed using t-tests, while Pearson’s χ2 tests were used for categorical variables. Logistic regression analyses examined the relationship between histopathologic characteristics and clinical outcomes. There was a statistically significant association between infiltrative tumors and a FMX-SR in comparison to non-infiltrative tumors (p < 0.001). Tumors with FMX-SR were significantly more deeply invasive (p=0.0025) and more likely to have LNI (p=0.0364), extranodal extension (p=0.0227) and PNI (p=0.0011) compared to tumors without FMX-SR. For cases with negative surgical margins, the association between tumors with FMX-SR and LNI was significantly strengthened (OR=4.73, p=0.0042), even after adjustments for age, race and DOI (OR=4.34, p=0.0154). Presence of both FMX-SR and infiltrative pattern of invasion in tumors with negative margins was significantly associated with LNI (p=0.0235) and recurrence (p=0.0124). These results suggest that interactions between nerve, tumor, and stromal cells play a role in tumor progression and represent additional prognostic factors that help stratify those patients at highest risk for LNI, extranodal extension and recurrence.