The diagnosis of invasive aspergillosis (IA) in patients with hematologic disorders is not straightforward; lack of sensitive and specific noninvasive diagnostic tests remains a major obstacle for establishing a precise diagnosis. In a series of 362 consecutive high-risk treatment episodes that were stratified according to the probability of IA based on recently accepted case definition sets, the potential for diagnosis of serial screening for circulating galactomannan (GM), a major aspergillar cell wall constituent was validated. After incorporating postmortem findings to allow a more accurate final analysis, this approach proved to have a sensitivity of 89.7% and a specificity of 98.1%. The positive and negative predictive values equaled 87.5% and 98.4%, respectively. False-positive reactions occurred at a rate of 14%, although this figure might be overestimated due to diagnostic uncertainty. More or less stringent criteria of estimation could highly influence sensitivity, which ranged from 100% to 42%; the impact on other test statistics was far less dramatic. All proven cases of IA, including 23 cases confirmed after autopsy only, had been detected before death, although serial sampling appeared to be necessary to maximize detection. The excellent sensitivity and negative predictive value makes this approach suitable for clinical decision making. Unfortunately, given the species-specificity of the assay, some emerging non-Aspergillus mycoses were not detected. In conclusion, serial screening for GM, complemented by appropriate imaging techniques, is a sensitive and noninvasive tool for the early diagnosis of IA in high-risk adult hematology patients.