Objectives were to investigate changes in transcriptome of PBL occurring at the onset of implantation and how they are affected by fertility stressors. Lactating cows (n = 481) had estrous cycle and ovulation synchronized to receive their first insemination (AI) postpartum. On d 19 after AI, PBL were isolated and mRNA extracted. A subsample of PBL mRNA from 36 cows was subjected to transcriptome analysis using the Affymetrix platform. Pregnancy was diagnosed on d 34 after AI. Two fertility stressors were evaluated, progesterone concentration during development of the ovulatory follicle and clinical uterine diseases (UTD). At the onset of synchronization, experimental design was established to have cows ovulating follicles that grow under low (LP) or high (HP) concentrations of progesterone. In addition, cows were evaluated daily on the first 10 d postpartum for diagnosis of UTD. Statistics was performed using Limma on R and FDR adjustment was used. LP during development of the ovulatory follicle reduced pregnancy per AI (P/AI; 34 vs 53%) and altered the transcriptome of PBL. In the HP group, pregnancy resulted in upregulation of classical interferon stimulated genes (e.g., IFI6, ISG15, OAS1Y); whereas in the LP group, pregnancy resulted in downregulation of a large number of inflammatory response genes (e.g., HP, JUN, MYD88). Particularly distinct transcriptome was observed in LP cows that failed to become pregnant, which indicated an inflammatory state. Cows that suffered from UTD also presented reduced P/AI (33 vs 50%) but only subtle differences in transcriptome, although potentially important. In pregnant cows previously diagnosed with UTD, expression of OAS1X was downregulated whereas CD244 was upregulated compared with pregnant cows not diagnosed with UTD. Fertility stressors were associated with altered PBL transcript profiles at the onset of implantation. Differences observed might represent either a primary cause of subfertility or a consequence of impaired developmental potential of their conceptus and its ability to secrete signaling molecules to modulate the maternal immune system.