Intra-abdominal infections can be classified into uncomplicated or complicated (peritonitis). Peritonitis is divided into primary, secondary, and tertiary. Tertiary peritonitis is the less common but the most severe among peritonitis stratifications, being defined as a recurrent intra-abdominal infection that occurs 48 h after a well-succeeded control of a secondary peritonitis. This disease has a complex pathogenesis that is closely related to the capacity of the peritoneal cavity to activate immunological processes. Patients who progress to persistent peritonitis are at an increased risk of developing several infectious complications such as sepsis and multiple organ failure syndrome. Moreover, tertiary peritonitis remains an important cause of hospital death mainly among patients with associated risk factors. The microbiological profile of organisms causing tertiary peritonitis is often different from that observed in other types of peritonitis. In addition, there is a high prevalence of multidrug-resistant pathogens causing this condition, and an appropriate and successful clinical management depends on an early diagnosis, which can be made easier with the use of clinical scores presenting a good prediction value during the intensive care unit admission. Complementarily, immediate therapy should be performed to control the infectious focus and to prevent new recurrences. In this sense, the treatment is based on initial antimicrobial therapy and well-performed peritoneal drainage.