We present a transcriptomic analysis aimed at investigating whether the changes in gene expression that occur under inbreeding generally reduce or enhance inbreeding depression. Discerning between these two alternatives can be addressed only when both changes in expression due to inbreeding and to inbreeding depression are estimated simultaneously. We used Affymetrix 2.0 arrays to study the changes in gene expression associated with both inbreeding and inbreeding depression for fitness in four sets of inbred sublines of Drosophila melanogaster. We found that for most genes showing changes in expression associated with inbreeding, the least depressed sublines were those showing the largest departures in expression from that of the outbred control. This suggests a pattern consistent with a protective role of expression changes against inbreeding effects, and would reveal a new dimension of the transcriptomics of inbreeding. The variation in depression observed could then be due not only to the genetic damages primarily originating that depression, but also possibly to differences in the ability to carry out the appropriate adjustments in gene expression to cope with the inbreeding. We also found that these expression changes with a putative protective role against inbreeding effects show a clear specificity on RNA synthesis and splicing and energy derivation functions.