How central and peripheral chemoreceptor drives to breathe interact in humans remains contentious. We measured the peripheral chemoreflex sensitivity to hypoxia (PChS) at various isocapnic CO2 tensions (PCO2${P_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}}}$) to determine the form of the relationship between PChS and central PCO2${P_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}}}$. Twenty participants (10F) completed three repetitions of modified rebreathing tests with end‐tidal PO2${P_{{{\mathrm{O}}_{\mathrm{2}}}}}$ (PETO2${P_{{\mathrm{ET}}{{\mathrm{O}}_{\mathrm{2}}}}}$) clamped at 150, 70, 60 and 45 mmHg. End‐tidal PCO2${P_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}}}$ (PETCO2${P_{{\mathrm{ETC}}{{\mathrm{O}}_{\mathrm{2}}}}}$), PETO2${P_{{\mathrm{ET}}{{\mathrm{O}}_{\mathrm{2}}}}}$, ventilation (V̇$\dot{V}$E) and calculated oxygen saturation (SCO2) were measured breath‐by‐breath by gas‐analyser and pneumotach. The V̇$\dot{V}$E–PETCO2${P_{{\mathrm{ETC}}{{\mathrm{O}}_{\mathrm{2}}}}}$ relationship of repeat‐trials were linear‐interpolated, combined, averaged into 1 mmHg bins, and fitted with a double‐linear function (V̇$\dot{V}$ES, L min−1mmHg−1). PChS was computed at intervals of 1 mmHg of PETCO2${P_{{\mathrm{ETC}}{{\mathrm{O}}_{\mathrm{2}}}}}$ as follows: the difference in V̇$\dot{V}$E between the three hypoxic profiles and the hyperoxic profile (∆V̇$\dot{V}$E) was calculated; three ∆V̇$\dot{V}$E values were plotted against corresponding SCO2; and linear regression determined PChS (Lmin−1mmHg−1%SCO2−1). These processing steps were repeated at each PETCO2${P_{{\mathrm{ETC}}{{\mathrm{O}}_{\mathrm{2}}}}}$ to produce the PChS vs. isocapnic PCO2${P_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}}}$ relationship. These were fitted with linear and polynomial functions, and Akaike information criterion identified the best‐fit model. One‐way repeated measures analysis of variance assessed between‐condition differences. V̇$\dot{V}$ES increased (P < 0.0001) with isoxic PETO2${P_{{\mathrm{ET}}{{\mathrm{O}}_{\mathrm{2}}}}}$ from 3.7 ± 1.5 L min−1mmHg−1 at 150 mmHg to 4.4 ± 1.8, 5.0 ± 1.6 and 6.0 ± 2.2 Lmin−1mmHg−1 at 70, 60 and 45 mmHg, respectively. Mean SCO2 fell progressively (99.3 ± 0%, 93.7 ± 0.1%, 90.4 ± 0.1% and 80.5 ± 0.1%; P < 0.0001). In all individuals, PChS increased with PETCO2${P_{{\mathrm{ETC}}{{\mathrm{O}}_{\mathrm{2}}}}}$, and this relationship was best described by a linear model in 75%. Despite increasing central chemoreflex activation, PChS increased linearly with PETCO2${P_{{\mathrm{ETC}}{{\mathrm{O}}_{\mathrm{2}}}}}$ indicative of an additive central–peripheral chemoreflex response. Key points: How central and peripheral chemoreceptor drives to breathe interact in humans remains contentious.We measured peripheral chemoreflex sensitivity to hypoxia (PChS) at various isocapnic carbon dioxide tensions (PCO2${P_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}}}$) to determine the form of the relationship between PChS and central PCO2${P_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}}}$.Participants performed three repetitions of modified rebreathing with end‐tidal PO2${P_{{{\mathrm{O}}_{\mathrm{2}}}}}$ fixed at 150, 70, 60 and 45 mmHg. PChS was computed at intervals of 1 mmHg of end‐tidal PCO2${P_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}}}$ (PETCO2${P_{{\mathrm{ETC}}{{\mathrm{O}}_{\mathrm{2}}}}}$) as follows: the difference in V̇$\dot{V}$E between the three hypoxic profiles and the hyperoxic profile (∆V̇$\dot{V}$E) was calculated; three ∆V̇$\dot{V}$E values were plotted against corresponding calculated oxygen saturation (SCO2); and linear regression determined PChS (Lmin−1mmHg−1%SCO2−1).In all individuals, PChS increased with PETCO2${P_{{\mathrm{ETC}}{{\mathrm{O}}_{\mathrm{2}}}}}$, and this relationship was best described by a linear (rather than polynomial) model in 15 of 20.Most participants did not exhibit a hypo‐ or hyper‐additive effect of central chemoreceptors on the peripheral chemoreflex indicating that the interaction was additive. [ABSTRACT FROM AUTHOR]