Clinical syndromes caused by Salmonella infection in humans are divided into typhoid fever, caused by Salmonella typhi and Salmonella paratyphi, and a range of clinical syndromes, including diarrhoeal disease, caused by a large number of non-typhoidal salmonella serovars (NTS). Typhoid is a human-restricted and highly adapted invasive disease, but shows little association with immunocompromise. In contrast, NTS have a broad vertebrate host range, epidemiology that often involves food animals, and have a dramatically more severe and invasive presentation in immunocompromised adults, in particular in the context of HIV. Immunocompromise among adults, including underlying severe or progressive disease, chronic granulomatous disease, defects or blockade of specific cytokines (particularly IL-12/IL-23/IL-17 and TNF), and HIV, is associated with suppurative foci and with primary bacteraemic disease, which may be recurrent. These patients have markedly increased mortality. Worldwide, invasive recurrent NTS bacteraemia associated with advanced HIV disease is a huge problem, and the epidemiology in this context may be more human-restricted than in other settings. This review will describe the presentation and pathogenesis of NTS in different categories of immunocompromised adults, contrasted to typhoid fever.