Cattle of the same breed from different regions of the USA may have altered responses to heat stress and fescue toxicosis. Angus steers from Missouri (MO ANG, n = 10, 513.6 ± 13.6 kg BW) and Oklahoma (OK ANG, n = 10, 552.8 ± 12.0 kg BW) were fed a diet containing either endophyte-infected (E+, 30 μg ergovaline/kg BW/day) or endophyte-uninfected (E−, 0 μg ergovaline/kg BW/day) tall fescue seed for 23 days. Diet treatment began on day 2. Animals were maintained at thermoneutrality (TN, 19–22 °C, days 1–8) and then exposed to heat stress (HS, cycling 26–36 °C, days 9–22). On day 23, ambient temperature was returned to TN and used as a recovery day. Feed intake (FI) was measured daily, with rectal and skin temperatures determined six times daily. Feed intake reduction from pretreatment levels was greater (P < 0.01) for E + (13.9 ± 0.9 versus 11.9 ± 0.3 kg/day) compared to E − (12.6 ± 0.9 versus 12.4 ± 0.3 kg/day) steers over the entire TN period, regardless of Angus group. During HS, E + cattle had reduced FI (P < 0.02; 6.9 ± 0.2 versus 8.4 ± 0.2 kg/day) compared to E − animals, independent of region of origin. A greater decrease in FI (P < 0.01) was observed for OK (12.1 ± 0.3 versus 6.2 ± 0.2 kg/day) compared to MO ANG (12.2 ± 0.3 versus 7.9 ± 0.2 kg/day) when ambient temperature was increased from TN to HS. On day 13 and days 15–22, OK ANG (E+) had reduced FI (P < 0.01, −2.21 kg) compared to OK ANG (E−), while there was no effect on MO ANG. From day 12 to day 22 of HS, daily minimum temperatures for ear, rump, and tail skin were less for E + (P < 0.05) when compared with E−treated steers, signifying peripheral vasoconstriction in E + animals. This was supported by reduced shoulder and lower tail temperatures (P < 0.01) for E + compared to E−treated OK ANG on the recovery day. In summary, regional differences in the response to fescue toxicosis exist, with peripheral vasomotor effects becoming most evident when animals are subjected to rapid changes in their environment.