Necrotic enteritis (NE) continues to be a significant burden to the poultry industry, compounded by pressure to reduce antibiotic use. Researchers use NE-challenge models to study the infection biology of NE and as screening tools to develop potential novel interventions. Currently, data are limited comparing such models between research establishments, and few indicate which quantitative metrics provide the most accurate measure for determining the efficacy of interventions. We compared data from 10 independent NE-challenge trials incorporating six challenge models employed in four geographical regions to determine the extent of variability in bird responses and to determine, using principal component analysis (PCA), which variables discriminated most effectively between nonchallenged control (NC) and challenged control (CC) groups. Response variables related to growth performance (weight gain, feed intake, feed conversion), health (mortality, lesion scores, NE induction rate), and, in three trials only, gut integrity (tight junction protein claudin-1, claudin-2, and zonula occludens-1 expression, coccidia counts, and intestinal permeability [assessed by FITC-dextran assay]). Treatments included a CC, which varied between trials (for example, in Eimeria predisposition, Clostridium perfringens strain, and days of inoculation), and a NC. The degree of response to challenge in CC birds varied significantly among models and trials. In all trials, lesion scores 1 to 4 days postchallenge were increased in CC vs. NC birds and varied both within and among models (by 0.29-1.17 points and 0.05-2.50 points, respectively). In addition, NE-related mortality at day 28 was increased in CC vs. NC, both within and among models (by 1.79%-4.72% and 0.02%-16.70%, respectively), and final (day 35 or 42) body weight was reduced by 3.9%-14.4% and overall FCR increased by up to 27% across trials (P , 0.05). A PCA on the combined dataset including only performance indicators failed to adequately differentiate NC and CC groups. However, the combination of performance and gut integrity variables and standardization of data by trial and phase achieved greater resolution between groups. This indicated that the inclusion of both types of variables in future NE-challenge studies would enable the generation of more robust predictions about intervention efficacy from different types of infection models. A final PCA based on a subset of key indicator variables, including body weight, feed intake, feed conversion ratio, mortality, and lesion score, achieved a good level of separation between NC and CC status of birds and could, with further research, be a useful supplement to existing approaches for assessing and predicting the NE status of birds in the field.