Background Feed restriction occurs frequently during pig growth, either due to economic reasons or stressful environmental conditions. Local breeds are suggested to have better tolerance to periods of feed restriction. However, the mechanisms underlying the response to feed restriction in different breeds is largely unknown. The aims of the present study were (1) to compare the blood transcriptome profile in response to feed restriction and refeeding of two contrasted breeds, Large White (LW), which has been selected for high performance, and Creole (CR), which is adapted to tropical conditions, and (2) to investigate the effect of a moderate feed restriction and refeeding on whole blood transcriptome. Analysis of blood transcriptome allows to study the response to feed restriction and refeeding in a dynamic way. RNAseq was performed on blood samples of growing LW and CR pigs at two time points: after 3 weeks of feed restriction and after 3 weeks of refeeding. The data was compared with samples from control animals offered the same diet on an ad libitum basis throughout the whole experiment. Results In terms of performance (body weight and feed efficiency), CR pigs were less impacted by feed restriction than LW. The transcriptional response to feed restriction and refeeding between CR and LW was contrasted both in terms of number of DEGs and enriched pathways. CR demonstrated a stronger transcriptional response to feed restriction whereas LW had a stronger response to refeeding. Differences in the transcriptional response to feed restriction between CR and LW were related to cell stress response (Aldosterone Signalling, Protein ubiquitination, Unfolded Protein Signalling) whereas after refeeding, differences were linked to thermogenesis, metabolic pathways and cell proliferation (p38 MAPK, ERK/MAPK pathway). In both breeds, transcriptional changes related to the immune response were found after restriction and refeeding. Conclusions Altogether, the present study indicates that blood transcriptomics can be a useful tool to study differential genetic response to feed restriction in a dynamic way. The results indicate a differential response of blood gene expression to feed restriction and refeeding between breeds, affecting biological pathways that are in accordance with performance and thermoregulatory results.