Background: Complicated diverticulitis (CD) is a common problem for surgeons. In treating it, as a general principle, every verified source of infection should be controlled. Supplementary antimicrobial management involves a delicate balance of optimizing empirical therapy while reducing unnecessary antibiotic use. The necessity to know the most frequent infecting pathogens and their spectra of resistance is becoming pivotal. The aim of this study was to determine the microbiologic profile of complicated intra-abdominal infections (IAIs) secondary to CD, to analyze the role of empirical antimicrobial therapy, and to describe the clinical aspects of CD worldwide. Material and Methods: The study derives from two multicenter prospective observational studies: CIAO (Complicated Intra-Abdominal infection Observational study) and CIAOW (Complicated Intra-Abdominal infection Observational World" study). The aim of the study was to analyze the intra-abdominal bacteriology in complicated diverticulitis and its relation to the clinical outcome. Results: The 272 patients had a mean/median age of 66.3 ± 14.9 (standard deviation; SD) and 69 (range 18-99). Patients >70 years old totaled 122 (44.9%). Conditions at admission were sepsis in 113 patients (41.5%) and severe sepsis and septic shock in 37 (13.6%) and 21 (7.7%), respectively; and localized peritonitis in 148 patients (54.4%), whereas in 124 (45.6%), the condition was generalized. Some 94 patients (34.6%) experienced a delay in initial intervention (>24 h). The mean and median duration of antimicrobial therapy were 12.3 ± 8.7 (standard deviation) and 10 (range 1-59) days. A total of 162 patients (59.6%) obtained adequate empirical antibiotic therapy, and 96 patients (35.3%) were admitted to the intensive care unit (ICU). The 30-day mortality rate was 12.1%. A total of 311 bacteria were isolated: 136 (43.7%) gram-negative, 76 (24.4%) gram-positive, 22 (7%) fungi, and 77 (24.7%) anaerobes. Of the 363 bacteria isolated, 22 (7%) were drug resistant. Four of these infections (22.2%) were health-care-associated and 18 (5.7%) community-acquired. By univariable analysis, the only statistically significant factor associated with resistant bacteria was inadequacy of the empirical antimicrobial therapy (p = 0.004). The factors associated with death were delay in initial intervention (p = 0.006) and ICU admission because of severe sepsis on admission (p = 0.004). Conclusion: Early source control is mandatory to reduce the mortality rate in complicated diverticulitis. Effective empirical antimicrobial agent therapy is necessary to reduce resistance and improve the clinical outcome.