The SAMPL9 host-guest challenge provided a platform to test the accuracy and reliability of computational methods for predicting BFEs on a set of 13 guests to WP6, and 5 phenothiazine based drugs to bCD and HbCD. Participants had some level of success on the WP6 dataset whereas the cyclodextrin challenge was particularly troublesome. In general, ranked BFE predictions for WP6 were more accurate and had better correlation with experiment compared to the cyclodextrin-phenothiazine set. Correlation metrics for ranked methods in the cyclodextrin dataset were poor with R 2 and t values well below 0.5. Overall, the predictive performance of the majority of methods in WP6 dataset was statistically similar to one another, and likewise for the methods in the cyclodextrin dataset. SMD and MM-PBSA / GBSA endpoint calculations in the cyclodextrin challenge were an exception, where BFEs were estimated significantly too favorable by over 10 kcal/mol. These differences in performance across host families are in keeping with prior SAMPL challenges, where often predictions for one host family seem easier than others, and this remained true here.