Increased ambient particulate matter (PM) is associated with adverse cardiovascular and respiratory outcomes as demonstrated by epidemiology studies. Several studies have investigated the role of co-pollutants, such as ozone (O₃), in this association. It is accepted that physiological adaptation involving the respiratory system occurs with repeated exposures to O₃. We hypothesize that adaptation to PM and O₃ varies among different inbred mouse strains, and cardiopulmonary adaptation to O₃ is a synchronized response between the cardiac and respiratory systems. Heart rate (HR), heart rate variability (HRV), and the magnitude and pattern of breathing were simultaneously measured by implanted telemeters and by plethysmography in three inbred mouse strains; C57Bl/6J (B6), C3H/HeJ (HeJ) and C3H/HeOuJ (OuJ). Physiological responses were assessed during dual exposures to filtered air, O₃ (576 ± 32 ppb) and/or carbon black (CB, 556 ± 34 µg/m³). Exposures were repeated for 3 consecutive days. While each strain showed significant reductions in HR during CB with O₃ pre-exposure (O₃CB) on day 1, prominent HRV responses were observed in only HeJ and OuJ mice. Each strain also differed in their adaptation profile in response to repeated O₃CB exposures. Whereas B6 mice showed rapid adaptation in HR after day 1, HeJ mice generally showed more moderate HR and HRV adaptation after day 2 of exposure. Unlike either B6 or HeJ strains, OuJ mice showed little evidence of HR or HRV adaptation to repeated O₃CB exposure. Adaptation profiles between HR regulation and breathing characteristics were strongly correlated, but these associations varied significantly among strains. These findings suggest that genetic factors determine the responsivity and adaptation of the cardiac and respiratory systems to repeated co-pollutant exposures. During O₃CB exposure, adaptation of cardiac and respiratory systems is markedly synchronized, which may explain a potential mechanism for adverse effects of PM on heart function.