Clonal hematopoiesis (CH) is defined by the acquisition of somatic leukemia-associated gene mutations in blood or bone marrow cells without signs of a hematological disease and is associated with an increased risk of blood cancers, cardiovascular disease, and higher all-cause mortality. In patients receiving chemotherapy for cancer, CH is associated with shorter overall survival (OS) and an increased risk of therapy-associated myeloid neoplasms. The present study investigates the role of CH in patients with metastatic colorectal cancer (mCRC) and patients with ischemic stroke. For this purpose, 237 mCRC patients were examined who were treated with FOLFIRI and cetuximab or bevacizumab as first-line therapy as part of the FIRE-3 (AIO KRK-0306) study. Furthermore, the clinical significance of CH in 581 patients of the PROSpective Cohort of Patients with Incident Stroke Berlin (PROSCIS-B, NCT01363856) was investigated. Whole blood DNA from blood samples was analyzed for the presence of mutations using an error-corrected targeted sequencing approach with a panel of 45 CH-relevant genes. The primary endpoint in the mCRC cohort was OS, primary endpoint in the PROSCIS cohort was a combined endpoint (CEP) of recurrent stroke, myocardial infarction, or death. Sequencing analysis revealed 119 somatic mutations with variant allele frequency (VAF) >1% found in 86 of 237 patients (36%) in the FIRE-3 cohort. CH was significantly more common in the group of patients who had previously been exposed to chemotherapy (50% vs. 33%, p= 0.04). Multivariate Cox regression showed an association of CH with improved OS (hazard ratio (HR) 0.64, 95% CI 0.46-0.89, p=0.007), especially in patients with DNMT3A mutations (HR 0.53, 95% CI 0.36-0.80, p=0.002). Patients with DNMT3A mutations were also more likely to have an early response to therapy (75% vs. 56%, p = 0.033). In the PROSCIS-B cohort there was a CH prevalence of 41%. CH was associated with macroangiopathic stroke, higher serum levels of proinflammatory markers (CRP and IL-6), and increased risk of the combined endpoint (HR 1.55, 95%-CI 1.04 - 2.31, p = 0.03). In summary, these results reveal important new clinical associations of CH in the context of malignant and cardiovascular diseases. This work provides crucial results that can be investigated in further molecular exploratory studies and prospective clinical cohorts.