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Diseases caused by rickettsiae, which are vector-borne bacteria, vary widely from mild and self-limiting, to severe and life-threatening. Factors influencing this diversity of outcome are related to the host, to the infectious agent and to the treatment used to treat the infection. A literature search was conducted on PubMed using the phrases "factors-related severity, outcome, host, pathogen, Rickettsia conorii, R. rickettsii, R. africae, R. felis, R. prowazekii, R. typhi, genomics". Among host factors, old age and the male gender have been associated with poor outcome in rickettsioses. Co-morbidities, ethnical factors and the genetic background of the host also seem to influence the outcome of rickettsial diseases. Moreover, although the degree of the host response is beneficial, it could also partly explain the severity observed in some patients. Among pathogen-related factors, traditional concepts of factors of virulence had been challenged and genomic reductive evolution with loss of regulatory genes is the main hypothesis to explain virulence observed in some species, such as Rickettsia prowazekii, the agent of epidemic typhus. R. prowazekii is the more pathogenic rickettsiae and harbours the smaller genome size (1.1 Mb) compared to less or non-virulent species, and is not intracellularly motile, a factor considered as a virulence factor for other intracellular bacteria. The antibiotic regimen used to treat rickettsioses also has an influence on prognosis. Usual concepts of severity and virulence in rickettsioses are challenging and are frequently paradoxical. In this mini-review, we will describe factors currently thought to influence the outcome of the main rickettsioses responsible for illness in humans.