Inbred mice develop strain-dependent changes in sleep during the first few days after inoculation with influenza virus. To identify genes with the potential to differentially modulate sleep under this condition, we performed complementary DNA microarray analysis of both lung and basal forebrain (BF) of infected (I) and uninfected BALB/cByJ (C) and C57BL/6J (B6) mice. This analysis showed significant variation in the expression pattern of 667 and 1217 of the surveyed genes in BF and lung, respectively (P < 0.01). Applying the additional criterion of an effect size >or=2, 495 genes differed in expression in lung compared with 204 in BF. In BF, more genes were differentially expressed as a function of mouse strain, whereas in lung, more genes were differentially expressed as a function of health status. Significant alterations in expression after infection were more numerous and robust in BALB/cByJ vs. C57BL/6J mice. Some genes showed significant variation in both tissues as a function of strain or condition, but the changes in general were not parallel. Genes that showed significant and robust variation as a function of strain, health status or tissue included those related to immune function, metabolism, signal transduction, cell cycle regulation, apoptosis and other miscellaneous categories. Different patterns of gene expression in BF of uninfected mice suggest the possibility of fundamental mechanistic differences in pathways that modulate vigilance in these strains, whereas differences in expression of lung of infected mice suggests different peripherally generated sleep-modulatory stimuli in the two strains.