Introduction: Irritable bowel syndrome (IBS) and diverticulitis share clinical features. Misdiagnosed diverticulitis can cause unnecessary antibiotic therapy. Among IBS and non-IBS patients, we compared outpatient, clinically diagnosed (no computed tomography) diverticulitis rates. Among primary-care, diverticulitis-diagnosed IBS patients, we assessed imaged diverticulosis and probable misdiagnosed diverticulitis. Methods: Among 3836-patient IBS and 67,827-patient non-IBS cohorts identified from 2000 to 2002, we retrospectively compared the frequency of outpatient, clinically diagnosed, antibiotic-treated diverticulitis from 2003 to endpoints of December 31, 2017, disenrollment, or death. In IBS patients, we reviewed records of initial, primary care-managed episodes for misdiagnosis. Results: In 3836 clinically diagnosed IBS and 63,991 non-IBS cohorts, followup (median [interquartile range]) was 12.4 (3.9 to 15.0) years versus 10.2 (3.0 to 15.0) years, respectively (P < .001). The incidence rate/1000 patient-years (95% CI) of diagnosed diverticulitis was 14.0 (12.1 to 16.3) and 4.2 (4.0 to 4.5), respectively, (crude incidence rate ratio, 3.3 [2.8-3.9]; P <. 001). Of examined features, the diagnosis of IBS was most strongly associated with clinically diagnosed diverticulitis (adjusted incidence rate ratio [95% CI]; 2.64 [2.21-3.15], P < .001). Of initial diverticulitis diagnoses in 189 IBS patients, objective evidence-based diagnosis revision or exclusion occurred in 12 (6.3%), including 6 hospitalized; 29 (15.3%) had colon imaging before and/or afterward without diverticulosis reported; 143 (75.1%) had image-documented diverticulosis; and 6 (3.2%) had no imaging. Conclusions: Outpatient, clinically diagnosed, antibiotic-treated diverticulitis was increased 3-fold in IBS patients. Primary care clinical misdiagnosis of initial episodes occurred in 1 of 5 patients, but additional misdiagnosis due to misattribution of IBS pain to diverticulitis is suggested.