Deficiencies in neutrophil NADPH oxidase proteins have been demonstrated in humans with chronic granulomatous disease. However, no spontaneous mutation in murine NADPH oxidase has been reported. In this study we report that neutrophils from the diabetic mouse strains, C57BL/6J-m heterozygous lean (lepr^db/+) and homozygous obese (lepr^db/db) mice produced no superoxide on stimulation. An absence of intact p47^phox but not other oxidase proteins was observed in both mouse strains through the use of immunoblotting. Molecular analysis by reverse transcriptase-polymerase chain reaction identified three abnormal p47phox mRNA transcripts. Sequencing of genomic DNA of p47^phox revealed a point mutation at the –2 position of exon 8, which is consistent with aberrant splicing of the p47^phox transcript. These results indicate that the C57BL/6J-m db/db and db/+ mice are the first spontaneously derived murine model of NADPH oxidase deficiency involving a p47^phox mutation. J. Leukoc. Biol. 67: 210–215; 2000.