ISO 10993-4 in vivo thrombogenicity testing is required for regulatory approval of all blood-contacting medical devices and is often a key part of submission packages. Given the current state of in vivo thrombogenicity assays, the industry needs a more robust and reproducible assay design including in vitro models. This study describes an in vitro assay which integrates freshly-harvested ovine blood containing minimal heparin in a closed pumped loop. To confirm the reproducibility of this assay, control materials were identified which elicited either a positive or a negative thrombogenic response. These controls were used over a 13 month period, successfully demonstrating reproducibility in the resulting thrombogenicity scores, and were then used in a head-to-head comparison with an in vivo thrombogenicity study using a marketed, approved catheter as test article. Thrombogenicity scoring with the positive and negative controls was consistent over the 24 independent assays with >95% confidence (p = 1.0 for negative controls and p = 0.55 for positive controls) when in vitro results were compared to the in vivo assay. This in vitro blood loop method allows prediction of a materials' in vivo thrombogenicity, can substantially de-risk the materials or coating selection process and should replace the in vivo models currently in use.