A high proportion of the patients with Salmonella enterica serotype Typhi infection develop severe sepsis. The mortality rate is high despite aggressive antimicrobial therapy in these patients. The case of a 10-year-old boy who developed thrombocytopenia-associated multiple organ failure (TAMOF) secondary to S. typhi infection is reported. The patient did not respond to antimicrobial treatment, including ciprofloxacin, in addition to conventional supportive measures, so plasma exchange was performed. The thrombocytopenia and organ failure had resolved after 3 days of plasma exchange therapy. Plasma exchange is suggested to be a life-saving intervention in a child with TAMOF secondary to S. typhi infection.