Periods of intense physical training are associated with an increased incidence of infection. We hypothesize that the TLR pathways involved in the initial response to multiple pathogens are compromised during intense physical exercise stress. In order to test this hypothesis, eight male collegiate wrestlers participated in one month of intense physical conditioning stress. Blood was collected at rest both before and after a 1 month period of intense exercise, and after completing a single 90 minute session of exhaustive exercise. TLR receptor pathway expression was assessed by microarray. The results showed that 1 month of intense exercise conditioning decreased expression of genes that may be important in antiviral defense (IFN-alpha, TLR3, PKRKA, SARM1), and inflammatory response (TNFSRF, PTGS2, REL). Ninety minutes of intense exercise decreased IFN-gamma and IRF1, but expression of TLR pathways associated with anti-bacterial defense increased (TLR5, TIRAP, PGLYRP2, LY86). These findings are consistent with epidemiological data suggesting an increased incidence of respiratory viral infections during periods of intense physical exercise stress. The results also implicate several genes important in inflammation, and further research is needed to determine whether these genes play a significant role in the recently reported anti-inflammatory effects of repeated exercise.