A global ocean general circulation model is used to estimate the magnitude of interannual variability in air-sea fluxes of CO2 and O2 from 1980–1998 and to examine the controlling mechanisms. The global variability in the air-sea flux of carbon (±0.5 × 1015 grams Carbon yr−1 (PgC yr−1)) is forced by changes of ΔpCO2 and wind speeds related to the El Niño/Southern Oscillation (ENSO) cycle in the equatorial Pacific. In contrast the air-sea O2 flux is controlled by two regions: the equatorial Pacific and North Atlantic. The model captures much of the interannual variability of the CO2 flux observed at Bermuda, with some correlation with the North Atlantic Oscillation (NAO) index. However, basin-scale air-sea CO2 flux anomalies are not correlated with the NAO due to a rapid neutralization of entrained DIC anomalies by biological uptake and export production in the subpolar gyre. CO2 flux variability estimates from our ocean model and the mean atmospheric inversion results of Bousquet et al.  are in broad agreement in the equatorial Pacific, but not in the North Atlantic. This model suggests that the projection of air-sea flux anomalies onto the large-scale, mean air-sea flux pattern in atmospheric inversions may lead to an overestimate of the flux variability in the extra-tropics where the patterns of variability do not correspond to those of the mean flux.