Abstract Rationale The demographics of patients with idiopathic pulmonary arterial hypertension (IPAH) are changing and this diagnosis is increasingly being made in older patients. However, diagnostic misclassifications are common as it may be difficult to differentiate between IPAH and pulmonary hypertension due to heart failure with preserved ejection fraction (PH-HFpEF). We investigated the hypothesis that the capillary pCO 2 (p c CO 2 ) may help distinguishing between idiopathic pulmonary arterial hypertension (IPAH) and pulmonary hypertension due to heart failure with preserved ejection fraction (PH-HFpEF). Methods In a cross-sectional study, we retrospectively assessed p c CO 2 levels (obtained from arterialized capillary blood at the time of diagnosis) from patients with IPAH or PH-HFpEF, respectively. Receiver operated characteristics (ROC) were used to determine the p c CO 2 level providing the best discrimination between these two conditions. P c CO 2 values were considered helpful if they were associated with a negative predictive value >0.9 to excluded either IPAH or PH-HFpEF. Results The study enrolled 185 patients, 99 with IPAH (74% female; age 47 ± 17 years; body mass index 26 ± 5 kg/m 2 , PAPm 53 ± 12 mmHg, PAWP 8 ± 3 mmHg), and 86 with PH-HFpEF (64% female; age 69 ± 10 years; body mass index 30 ± 6 kg/m 2 , PAPm 47 ± 10 mmHg, PAWP 21 ± 5 mmHg). P c CO 2 at time of diagnosis was 33 ± 4 mmHg in the IPAH group and 40 ± 5 mmHg in the PH-HFpEF group (p  41 mmHg. Conclusions P c CO 2 levels were significantly lower in IPAH compared to PH-HFpEF and may provide useful information in differentiating between both conditions.