1. Arterial blood acid-base status of unanesthetized, unrestrained guinea pigs was studied during 6 hr of exposure to 4, 8, 10 and 14.5% CO2. 2. During exposure to 4% CO2, blood pH was kept within the range of control values, despite significant increase of 5-8 mmHg in PaCO2. 3. Most of the changes in blood acid-base status occurred during the first 30-60 min of exposure to CO2, and only minor changes were observed during the remaining exposure period (up to 6 hr). 4. In-vivo CO2 titration curves were not linear over the CO2 range studied here. The slope of the in-vivo H+/PaCO2 line became much more steep at PaCO2 values higher than 65-75 mmHg. 5. The apparent whole body buffer value (beta = -delta HCO-3/delta pH), being 42.6 slykes after 1 hr for the 4-10% CO2 range, changed to -18.1 slykes when calculated for 1 hr at the 10-14.5% CO2 range. 6. It is concluded that guinea pigs can regulate their blood pH better than rats, rabbits, dogs and men when exposed for short periods to CO2 levels up to 10%. 7. When exposed to higher levels (14.5%) of CO2, they show a very limited capability for regulating their blood pH--much less than rats, rabbits and dogs.