Year-to-year variability in CO2 fluxes can yield insight into climate-carbon cycle relationships, a fundamental yet uncertain aspect of the terrestrial carbon cycle. In this study, we use global observations from NASA's Orbiting Carbon Observatory-2 (OCO-2) satellite for years 2015–2019 and a geostatistical inverse model to evaluate 5 years of interannual variability (IAV) in CO2 fluxes and its relationships with environmental drivers. OCO-2 launched in late 2014, and we specifically evaluate IAV during the time period when OCO-2 observations are available. We then compare inferences from OCO-2 with state-of-the-art process-based models (terrestrial biosphere model, TBMs). Results from OCO-2 suggest that the tropical grasslands biome (including grasslands, savanna, and agricultural lands within the tropics) makes contributions to global IAV during the 5 year study period that are comparable to tropical forests, a result that differs from a majority of TBMs. Furthermore, existing studies disagree on the environmental variables that drive IAV during this time period, and the analysis using OCO-2 suggests that both temperature and precipitation make comparable contributions. ... mehrTBMs, by contrast, tend to estimate larger IAV during this time and usually estimate larger relative contributions from the extra-tropics. With that said, TBMs show little consensus on both the magnitude and the contributions of different regions to IAV. We further find that TBMs show a wide range of responses on the relationships of CO2 fluxes with annual anomalies in temperature and precipitation, and these relationships across most of the TBMs have a larger magnitude than inferred from OCO-2. Overall, the findings of this study highlight large uncertainties in process-based estimates of IAV during recent years and provide an avenue for evaluating these processes against inferences from OCO-2.