Background <p>Esophageal squamous cell carcinoma (ESCC) is a common malignant tumor of the gastrointestinal tract with a high mortality rate. Although positive regulatory domain zinc finger protein 1 (PRDM1) has long been thought to play a key role especially in the differentiation of B cells, its role in ESCC has never been studied. This study aimed to examine the association between PRDM1 and ESCC clinical and pathological characteristics and prognosis.</p> Methods <p>Using immunohistochemical and reverse transcription quantitative polymerase chain reaction, we detected the expression level of PRDM1 in consecutive ESCC surgical resections from 163 patients. To interpret PRDM1 immunohistochemical positivity, we employed three methods: PRDM1 10 high-power field (HPF) positive cell count (PCC), PRDM1 1HPF PCC and PRDM1 positive hotspots (PPHs). Based on PPH assessment and histological morphology, we developed a novel histological grading scheme. To evaluate the relationship between PRDM1 differential expression and clinical–pathological parameters in ESCC, we used the chi-square test. To evaluate the relationship between PRDM1 expression and ESCC prognosis, we performed Kaplan–Meier survival analysis and Cox regression analysis.</p> Results <p>Immunohistochemical staining revealed that PRDM1 was expressed in tumor epithelium, stroma, and adjacent squamous epithelium in ESCC. And the expression level of PRDM1 in tumor epithelium significantly correlated with tumor differentiation (<i>P</i> &lt; 0.05) and was closely related to the patient prognosis (<i>P</i> &lt; 0.05). Moreover, survival analysis results indicated that our novel histological grading seem to be better than the traditional histological grading criteria in predicting the prognosis of ESCC patients.</p> Conclusions <p>PRDM1 holds promise as a novel indicator for ESCC, with potential application value in the histological grading, diagnosis, and prognostic assessment of this disease.</p>