The interannual variability of atmospheric CO2 growth rate shows remarkable correlation with the El Niño Southern Oscillation (ENSO). Here we present results from mechanistically based terrestrial carbon cycle model VEgetation-Global-Atmosphere-Soil (VEGAS), forced by observed climate fields such as precipitation and temperature. Land is found to explain most of the interannual CO2 variability with a magnitude of about 5 PgC yr−1. The simulated land-atmosphere flux has a detrended correlation of 0.53 (0.6 at the 2–7 year ENSO band) with the CO2 growth rate observed at Mauna Loa from 1965 to 2000. We also present the total ocean flux from the Hamburg Ocean Carbon Cycle Model (HAMOCC) which shows ocean-atmosphere flux variation of about 1 PgC yr−1, and it is largely out of phase with land flux. On land, much of the change comes from the tropical regions such as the Amazon and Indonesia where ENSO related climate anomalies are in the same direction across much of the tropics. The subcontinental variations over North America and Eurasia are comparable to the tropics but the total interannual variability is about 1 PgC yr−1 due to the cancellation from the subregions. This has implication for flux measurement network distribution. The tropical dominance also results from a “conspiracy” between climate and plant/soil physiology, as precipitation and temperature changes drive opposite changes in net primary production (NPP) and heterotrophic respiration (Rh), both contributing to land-atmosphere flux changes in the same direction. However, NPP contributes to about three fourths of the total tropical interannual variation and the rest is from heterotrophic respiration; thus precipitation appears to be a more important factor than temperature on the interannual timescales as tropical wet and dry regimes control vegetation growth. Fire, largely driven by drought, also contributes significantly to the interannual CO2 variability at a rate of about 1 PgC yr−1, and it is not totally in phase with NPP or Rh. The robust variability in tropical fluxes agree well with atmospheric inverse modeling results. Even over North America and Eurasia, where ENSO teleconnection is less robust, the fluxes show general agreement with inversion results, an encouraging sign for fruitful carbon data assimilation.