Background: To explore the potential role of computed tomography (CT) texture analysis and an imaging biomarker in differentiating primary gastro-intestinal lymphoma (PGIL) from gastro-intestinal adenocarcinoma (GIAC). Methods: A total of 131 patients with surgical pathologically PGIL and GIAC were enrolled in this study. Histogram parameters of arterial and venous phases extracted from contrast enhanced modified discrete cosine transform (MDCT) images were compared between PGIL and GIAC by Mann-Whitney U tests. The optimal parameters for differentiating these two groups were obtained through receiver operating characteristic (ROC) curves and the area under the curve (AUC) was calculated. Results: Compared with GIAC, in arterial phase, PGIL had statistically higher 5th, 10th percentiles (p = 0.003 and 0.011) and statistically lower entropy (p = 0.001). In the venous phase, PGIL had statistically lower mean, median, 75th, 90th, 95th percentiles, and entropy (p = 0.036, 0.029, 0.007, 0.001 and 0.001, respectively). For differentiating PGIL from GIAC, V-median + A-5th percentile was an optimal parameter for combined diagnosis (AUC = 0.746, p < 0.0001), and the corresponding sensitivity and specificity were 81.7 and 64.8%, respectively. Conclusion: CT texture analysis could be useful for differential diagnosis of PGIL and GIAC.