OBJECTIVE: We describe experiments designed to determine the feasibility of distinguishing known from novel associations based on a clinical dataset comprised of International Classification of Disease, V.9 (ICD-9) codes from 1.6 million patients by comparing them to associations of ICD-9 codes derived from 20.5 million Medline citations processed using MetaMap. Associations appearing only in the clinical dataset, but not in Medline citations, are potentially novel. METHODS: Pairwise associations of ICD-9 codes were independently identified in both the clinical and Medline datasets, which were then compared to quantify their degree of overlap. We also performed a manual review of a subset of the associations to validate how well MetaMap performed in identifying diagnoses mentioned in Medline citations that formed the basis of the Medline associations. RESULTS: The overlap of associations based on ICD-9 codes in the clinical and Medline datasets was low: only 6.6% of the 3.1 million associations found in the clinical dataset were also present in the Medline dataset. Further, a manual review of a subset of the associations that appeared in both datasets revealed that co-occurring diagnoses from Medline citations do not always represent clinically meaningful associations. DISCUSSION: Identifying novel associations derived from large clinical datasets remains challenging. Medline as a sole data source for existing knowledge may not be adequate to filter out widely known associations. CONCLUSIONS: In this study, novel associations were not readily identified. Further improvements in accuracy and relevance for tools such as MetaMap are needed to realize their expected utility.