The Delta F508 gene mutation prevents delivery of the cystic fibrosis transmembrane conductance regulator (CFTR) to the plasma membrane. The current study examines the biochemical basis for the upregulation of Delta F508 CFTR expression by sodium butyrate and low temperature. Surface CFTR protein expression was determined by quantitative immunoblot following surface biotinylation and streptavidin extraction, CF gene expression was measured by Northern analysis and CFTR function by forskolin-stimulated I-125 efflux, Butyrate increased Delta F508 mRNA levels and protein expression but did not increase the biochemical or functional expression of Delta F508 CFTR at the cell surface. Low temperature increased the biochemical and functional expression of Delta F508 CFTR at the cell. surface but did not increase CFTR mRNA levels. Combining treatments led to a synergistic increase in both Delta F508 mRNA and surface protein levels that results from the stabilization of CFTR mRNA and protein by low temperature. These findings indicate that surface expression of Delta F508 CFTR can be markedly enhanced by carefully selected combination agents.