The co-infection of infectious hematopoietic necrosis virus (IHNV) and infectious pancreatic necrosis virus (IPNV) with high mortality was observed in farmed rainbow trout (Oncorhynchus mykiss) in China. Severe extensive necrosis was observed on the major organs of moribund rainbow trout, and tissue fluid from diseased fish was able to cause obvious cytopathic effect in CHSE-214 cells. The co-infection of IHNV and IPNV was detected by RT-PCR and confirmed by an immunofluorescent assay test. The IHNV and IPNV in this co-infection had the same genogroups as the currently prevalent IHNV and IPNV strains in China, and they belonged to genogroup J and genogroup 1, respectively. Distinct from previous studies, the IHNV loads were significantly higher than the IPNV loads in both co-infected tissues and viral cell culture suspension (p < 0.05). Furthermore, the tissue suspensions and cell culture suspensions (cells directly inoculated with pooled tissues suspension from infected fish) were very virulent, causing cumulative mortalities of 94% and 96% in rainbow trout that were challenged at a standard dosage of 100 half tissue culture infective doses (TCID50). Similar high mortality was observed from rainbow trout challenged with purified IHNV, indicating mortality caused by natural co-infected samples may be solely attributable to IHNV, with no apparent impact from the IPNV in the co-infected sample. However, significantly decreased mortality was obtained from the artificial co-infection performed by challenging rainbow trout with a mixture of purified IHNV and purified IPNV at a 1:1 ratio. Notably, viral interference was not detected in this natural co-infection case, even though it could be observed in fish challenged with the purified viruses from the natural infection sample, indicating that IHNV and IPNV co-infection is far more complicated than previously understood. It is urgent to pay more attention to viral interactions to improve the systematic prevention and control of fish diseases.