This study was undertaken to determine the prevalence and pathogenic potential of Escherichia coli (E. coli) isolated from piglets having white score diarrhea as a result of outbreak occurred in Qinghai Tibetan Plateau in 2015. A total of 81 E.coli were isolated from 83 fecal samples. The organisms were inoculated on MacConkey agar and EMB agar and identified via biochemical tests. Polymerase chain reaction was used to detect representative virulence factors or genes, including E.coli adherence factor (K88, CS31A, afaE-8), toxins (estA, estB, Stxl, Stx2, EAST1), pathogenicity island (eaeA, irp2, ETT2) and outer membrane protein (ompA). Moreover O-antigen serotype was tested by slide agglutination test and a mouse model was built to assess the lethality of the E.coli isolates through subcutaneous-infection. Out of 81 E.coli isolates, the most prevalent gene detected was ompA (90.12%), followed by ETT2 (69.14%), irp2 (54.32%), EAST1 (46.91%), CS31A (41.98%), estB (19.75%), eaeA (14.81%), estA (12.35%) and K88 (1.23%), while others were negative. The result showed that the main serotypes of E. coli were O8, O64, O138, O157, O139 and O141, accounting for 60 (74.04%) of all strains, while mouse subcutaneous-infection model revealed that 45(55.56%) of the isolates were “killers”, 20 (24.69%) were pathopoiesia but not lead to die and 16 (19.75%) of the isolates were non virulent. This study reported the occurrence of pathogenic E. coli isolated from Tibetan piglets with white score diarrhea which highlights the threat of pathogenic E.coli in free ranging Tibetan piglets, as the local herdsmen can directly suffer a great economic loss.