D-dimer test combined with clinical probability assessment has been proposed as the first step in the diagnostic work-up of patients with suspected pulmonary embolism (PE). In a prospective management study we investigated the safety and efficiency of excluding PE by a normal D-dimer combined with a low or moderate clinical probability. Of the 202 study patients this combination ruled out PE in 64 (32%) patients. The 3-month thromboembolic risk in these patients was 0% (95% CI, 0.0-5.6%). The prevalence of PE in the entire cohort was 29% (59 patients), whereas in the low, moderate and high clinical probability groups this was 25%, 26% and 50%, respectively. We conclude that ruling out suspected PE by a normal D-dimer combined with a low or moderate clinical probability appears to be a safe and efficient strategy. The accuracy of the clinical probability assessment is modest.