Objective To analyze the clinical characteristics of fascioliasis and primary liver cancer patients, so as to provide insights into early differential diagnosis of these two diseases. Methdos The clinical data of 110 fascioliasis patients and 110 primary liver cancer patients admitted to The First Affiliated Hospital of Dali University during the period from January 1, 2014, to December 31, 2024 were collected, and the clinical characteristics, laboratory parameters, imaging features, and pathological manifestations were compared between the two groups. Comparisons of measurement data were done using t test or Mann-Whitney U test, while comparisons of count data were conducted with chi-square test or Fisher’s exact probability test. Results The onset date of fascioliasis patients was primarily distributed during the period from July to November, and the onset date of primary liver cancer patients was evenly distributed from January to December, without a clear-cut temporal distribution pattern. Fascioliasis patients were mainly from Dali Bai Autonomous Prefecture (62 cases, 56.4%), Lijiang City (15 cases, 13.6%), and Pu’er City (13 cases, 11.8%), and primary liver cancer patients mainly came from Dali Bai Autonomous Prefecture (84 cases, 76.4%), Nujiang Lisu Autonomous Prefecture (10 cases, 9.1%), and Baoshan City (9 cases, 8.2%). Fascioliasis patients had a disease course (from disease onset to healthcare seeking) of approximately 3 days to one year, which was longer than primary liver cancer patients (2 to 60 days). There were significant differences between fascioliasis and primary liver cancer patients in terms of age, gender distribution, proportion of a medical history of chronic viral hepatitis B, proportion of smoking, proportion of alcohol consumption, proportion of fever, proportion abdominal pain, proportion of abdominal distension, proportion of weight loss, alpha-fetoprotein level, carcinoembryonic antigen level, carbohydrate antigen 125 level, carbohydrate antigen 153 level, carbohydrate antigen 199 level, fibrinogen level, white blood cell count, neutrophils percentage, eosinophils percentage, absolute eosinophil count, hemoglobin level, platelet count, total bilirubin, direct bilirubin, indirect bilirubin, alanine aminotransferase activity, aspartate aminotransferase, gamma-glutamyl transpeptidase activity, and albumin level (t = 10.73, χ² = 48.6, 186.72, 41.56, 19.70, 42.49, 16.37, 5.74, 14.08, Z = -10.65, -3.03, -7.99, -6.05, -6.30, -2.65, -5.63, -10.20, -12.00, -12.05, -2.76, -7.75, -7.70, -8.00, -6.69, -4.79, -9.02, -4.91, -2.81, all P < 0.05). CT scans displayed multiple round-like low-density shadows in fascioliasis patients’ livers, which appeared a clustered distribution pattern; however, no enhancement was seen in the arterial phase following contrast enhancement. Contrast, abdominal CT scans displayed nodular low-density lesions with obvious enhancement in the arterial phase following contrast enhancement among primary liver cancer patients. In addition, the major pathological manifestations of fascioliasis patients included irregular tunnel-like necrosis, eosinophilic abscesses, and Charcot-Leyden crystals in the liver, while all primary liver cancer patients had a pathological type of hepatocellular carcinoma. Conclusion There are significant differences between fascioliasis and primary liver cancer patients in terms of time of disease onset, age distribution, gender ratio, laboratory parameters, imaging findings, and pathological characteristics. Combining epidemiological and clinical features may provide insights into early differential diagnosis.