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Cancer is associated with a prothrombotic state and venous thromboembolism (VTE) can be the first manifestation of occult cancer. However, no impact on survival of extensive cancer screening in VTE has been demonstrated. Limited data are available on the association between D-dimer (DD), a non-specific marker of activation of coagulation, at VTE diagnosis and occult cancer. The objective is to investigate whether high DD levels at VTE diagnosis are associated with subsequent cancer development. The study design is a retrospective cohort study conducted in a single tertiary care hospital from 2008 to 2018. The participants were consecutive patients diagnosed with symptomatic VTE and without known overt cancer who underwent routine clinical evaluation and laboratory tests. In case of abnormal findings, further targeted tests were performed. The primary outcome measures were cancer development within 12 months of VTE diagnosis. 843 patients (413 women-49%, median age 67.3 years; 10 lost to follow-up-1.2%) were included, of whom 567 (67%) had unprovoked VTE. Median DD was 2,750 ng/mL (range 30-45,320) and DD was above 8,000 ng/mL in 151 patients (18%). During follow-up, 37 patients (all above 60 years) developed new cancers (4.6 percent patient years; 95%CI 3.3-6.3). Multivariate regression showed that age above 60 years (Hazard Ratio-HR 11.7; 95%CI 1.58-86.6; p = 0.016) and DD above 8,000 ng/mL (HR: 2.5; 95%CI 1.22-5.24; p = 0.012) were independently associated with subsequent cancer development. Patients older than 60 years at VTE diagnosis may deserve extensive screening for occult cancer, and DD above 8000 ng/mL may be an index of occult cancer.