Cross‐protection is a phenomenon that occurs when infection with a mild virus prevents or suppresses the harmful effects of subsequent infection by a related severe virus. Isolates of Potato virus M (PVM, genus Carlavirus, family Betaflexiviridae), like isolates of other viruses, are likely to occur in plants in multiple infections, but the knowledge about intrahost interactions between PVM isolates and their impact upon the host response to infection is none. Here, we report that pre‐infection with a mild isolate I‐38 successfully protected Datura metel plants against destructive effects of infection by a severe isolate Uran. The latter was not detected by reverse transcription‐PCR in plants pre‐inoculated 7 days earlier by I‐38, which indicates that it was excluded by host defence mechanisms triggered by the low virulent isolate. Our results provide the first evidence for the occurrence of cross‐protection between PVM isolates within a common host plant.