The effects of proinflammatory pathway triggers on pregnancy success was assessed in early pregnant ewes. Effects of endogenous cytokine activation (via LPS), direct exogenous tumor necrosis factor-α (TNF-a) and TNF-a+Dexamethasone (TNF-a+Dex) administration were compared in regard to pregnancy rate. Dorset × Texel ewes (n = 38) were synchronized for estrus and bred to fertile rams (d 0). On d 6, ewes were assigned to receive via the jugular 2.5 mL containing either PBS (n = 9), 2.5 µg/kg LPS (n = 9), 1 µg/kg TNF-a (n = 10) at 0 and 30min, or 2.5 µg/kg of LPS after 3.5 mL containing 0.14 mg/kg BW im Dex (n = 10) at −12h and 0h. Behavioral changes and rectal temperatures (BT) were recorded before challenge and hourly for 12 h. Jugular blood was collected before challenge, every 30 min for 3 h, hourly until 12 h, at 24, 36, and 48 h, and on d 10 and d 26 for progesterone. At d 26, pregnancy was examined using ultrasonography. The proportion of ewes pregnant was analyzed by Chi-squared and Fisher’s exact test with preplanned contrasts. Other data were analyzed by repeated measures ANOVA. Treatment with LPS resulted in peak BT at 4 h (40°C; control 38°C; P < 0.05), increased lethargy, mucosal response, white blood cell (WBC) count (9.8 × 10⁶; control 9.1 × 10⁶; P < 0.05), serum TNF-a (0.9 ng/mL; control 0.2 ng/mL; P < 0.05). Treatment with LPS+Dex resulted in peak BT at 4 h (39°C), but was blunted by Dex. Additionally, Dex blocked mucosal and lethargic responses and attenuated LPS-induced increases in TNF-a and did not improve pregnancy rate compared with LPS alone (P > 0.05). TNF-a treatment increased BT at 1 h (39°C), did not induce lethargy; 5/10 ewes showed a mucosal response; and WBC counts did not change but high concentrations of TNF-a were not sustained. More control and TNF-a ewes (15/19) were pregnant than LPS or LPS+Dex ewes (9/19; P = 0.045). In summary, an inflammatory response was elicited by LPS and resulted in reduced proportion of ewes pregnant regardless of Dex administration. Treatment with TNF-a did not affect proportion of ewes pregnant, perhaps due to low serum TNF- a levels or different pathway components stimulated by LPS. These data show that a sustained inflammatory response to LPS decreased pregnancy rate and may involve a complex cascade of inflammatory mediators elicited by LPS.