(1) Background: Irritable bowel syndrome (IBS) represents one of the most common disorders of gut–brain interaction (DGBI). As recent data has suggested an increased cancer incidence for IBS patients, there is an ongoing debate whether IBS might be associated with a risk of cancer development. In the present study, we evaluated and compared incidence rates of different malignancies including gastrointestinal cancer in a large cohort of outpatients, with or without IBS, treated in general practices in Germany. (2) Methods: We matched a cohort of 21,731 IBS patients from the IQVIA Disease Analyzer database documented between 2000 and 2019 in 1284 general practices to a cohort of equal size without IBS. Incidence of cancer diagnoses were evaluated using Cox regression models during a 10-year follow-up period. (3) Results: In 11.9% of patients with IBS compared to 8.0% without IBS, cancer of any type was diagnosed within 10 years following the index date (p < 0.001). In a regression analysis, this association was confirmed in female (HR: 1.68, p < 0.001) and male (HR = 1.57, p < 0.001) patients as well as in patients of all age groups. In terms of cancer entity, 1.9% of patients with and 1.3% of patients without IBS were newly diagnosed with cancer of digestive organs (p < 0.001). Among non-digestive cancer entities, the strongest association was observed for skin cancer (HR = 1.87, p < 0.001), followed by prostate cancer in men (HR = 1.81, p < 0.001) and breast cancer in female patients (HR = 1.80, p < 0.001). (4) Conclusion: Our data suggest that IBS might be associated with cancer of the digestive organs as well as with non-digestive cancer entities. However, our findings do not prove causality and further research is warranted as the association could be attributed to life style factors that were not documented in the database.