OBJECTIVES: We present KNAVE-II, an intelligent interface to a distributed architecture specific to the tasks of query, knowledge-based interpretation, summarization, visualization, interactive exploration of large numbers of distributed time-oriented clinical data, and dynamic sensitivity analysis of these data. KNAVE-II main contributions to the fields of temporal reasoning and intelligent user interfaces are: (1) the capability for interactive computation and visualization of domain specific temporal abstractions, supported by ALMA--a computational engine that applies the domain knowledge base to the clinical time-oriented database. (2) Semantic (ontology-based) navigation and exploration of the data, knowledge, and temporal abstractions, supported by the IDAN mediator, a distributed architecture that enables runtime access to domain-specific knowledge bases that are maintained by expert physicians. METHODS AND MATERIALS: KNAVE-II was designed according to 12 requirements that were defined through iterative cycles of design and user-centered evaluation. The complete architecture has been implemented and evaluated in a cross-over study design that compared the KNAVE-II module versus two existing methods: paper charts and an Excel electronic spreadsheet. A small group of clinicians answered the same queries, using the domain of oncology and a set of 1000 patients followed after bone-marrow transplantation. RESULTS: The results show that users are able to perform medium to hard difficulty level queries faster and more accurately by using KNAVE-II than paper charts and Excel. Moreover, KNAVE-II was ranked first in preference by all users, along all usability dimensions. CONCLUSIONS: Initial evaluation of KNAVE-II and its supporting knowledge based temporal-mediation architecture, by applying it to a large data base of patients monitored several years after bone marrow transplantation (BMT), has produced highly encouraging results.