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Mucoepidermoid carcinomas (MECs) are a form of salivary gland malignancy. They are classified according to histological grade and perineural invasion (PNI). In another cancer subtypes, positive-PNI suggests increased poor prognosis; however, the role of isolated positive-PNI salivary gland MEC can still be better investigated as a risk factor. This study investigated whether isolated PNI is independently associated with poor outcomes. Retrospective study, cohort case-series, single-center hospital from 2009 to 2019. Patient demographics, primary tumor, intervention, and survival data are included. Univariate, multivariate, and Kaplan-Meier survival curve analyses were used for comparison.The study group consisted of 32 patients (15 PNI-positive tumors, and 17 PNI-negative tumors), all admitted for surgery. Univariate analysis showed differences in grade ( p  = 0.038), positive margins ( p  = 0.034), soft tissue invasion ( p  < 0.001), pathological stage ( p  = 0.014), recurrence ( p  = 0.015), distant metastasis ( p  = 0.015) and MEC related death ( p  = 0.015). The risk in PNI-positive patients to develop soft tissue invasion and positive surgical margins was OR  = 8.57 and OR  = 4.88, respectively. Multivariate analysis found age differences ( p  = 0.038), with OR  = 1.08. The Disease Specific Survival (DSS) was worst in the PNI-positive group ( log-rank p-value  = 0.0011), where the probability of dying occurred in the 12-24 months period ( log-rank p-value  = 0.002). PNI-positive salivary gland MEC is an independent prognostic factor, with poor DSS, increased locoregional recurrence, close correlation with a more aggressive pattern of the disease, and should be reviewed as a high grade histological criteria. Our findings may imply changes in the clinical approach with a more aggressive attitude in the overall treatment., Competing Interests: Conflict of interestThe authors declare no Competing Interests in this article., (© Association of Otolaryngologists of India 2021.)