Diet composition and nutrient balance can have a critical impact on intestinal integrity during exposure to enteric pathogens. Researchers have extensively reported benefits on nutrient availability and broiler performance as a consequence of the impact of phytase supplementation. However, the poultry industry has little information on the effects of phytase supplementation in disease settings. The objective of these studies was to evaluate phytase supplementation impact on bird performance, intestinal morphology and pH, nutrient digestibility and bone mineralization during necrotic enteritis (NE). In each experiment, Cobb 500 broilers were obtained from a commercial hatchery and housed in floor pens at the Virginia Tech Turkey Research Center. Birds were placed on used litter from a previous flock that had presented clinical signs of NE. Broilers were fed non-medicated diets formulated to meet NRC (1994) nutrient requirements, except for calcium and phosphorus. In the first experiment, birds began exhibiting clinical signs of NE on d 9, and elevated NE-associated mortality persisted until d 26. Mortality was influenced by the main effects of dietary Ca or phytase. Dietary Ca supplemented at 0.9% or 1000 FTU/kg of phytase increased mortality compared to 0.6% Ca or 0 FTU/kg phytase, respectively, from d 0 to 19. Feed intake (FI) and feed conversion (FC) were affected by Ca x P interaction. From d 0 to 19, birds fed 0.9% Ca and 0.3% available P (avP) had decreased FI and improved FC compared to birds fed 0.9% Ca and 0.45% avP, while FI and FC were similar in birds fed diets with 0.6% Ca, regardless of avP level. Calcium x P x phytase interaction influenced BW or BWG from d 0-12. In general, birds fed 0.9% Ca and 0.45% avP with phytase were heavier compared to birds fed 0.6% Ca, 0.45% avP, and phytase. Calcium at 0.9% increased gizzard (d 19) and jejunum (d 12) pH. Dietary Ca supplemented at 0.9%, avP supplemented at 0.45%, and 1,000 FTU/kg phytase significantly increased tibia ash weight compared to 0.6% Ca, 0.3% avP, and 0 FTU/kg phytase, respectively, on d 12. A 3-way interaction was observed on d 35 for tibia ash percentage; birds fed 0.9% Ca and 0.45% avP had a significant increase in tibia ash percentage, regardless of phytase supplementation. A 3-way interaction was also observed for Ca and P digestibility on d 35. Phytase supplementation significantly increased Ca digestibility regardless of Ca and P levels of the diets. In addition, diets containing 0.6% Ca and 1,000 FTU/Kg of phytase resulted in a significant increase in P digestibility, regardless of P levels. In the second experiment, birds also began exhibiting clinical signs of NE on d 9, and elevated NE-associated mortality persisted until the end of the trial (d 21). Mortality was significantly affected by an interaction between Ca source and Ca levels. Significantly higher mortality was observed when animals were fed 0.9% Ca diets formulated with calcified seaweed from d 0-21 compared to 0.6% Ca diets (regardless of Ca source). From d 0-7, birds fed 0.6% Ca in diets supplemented with phytase had heavier BW than the other treatments regardless of Ca source. From d 0-14 and 0-21, animals fed diets with calcified seaweed had significantly higher FC than animals fed diets with limestone. On d 21, the gizzard of birds fed 0.9% Ca was significantly less acidic than the gizzard of birds fed 0.6% Ca. In conclusion, reducing dietary levels of Ca associated with phytase supplementation improved bird performance and nutrient digestibility. In addition, these experiments indicate that Ca is an important dietary factor in the pathogenesis of NE.