The interannual variability of net sea–air CO2 flux for the period 1982–2007 is obtained from a diagnostic model using empirical subannual relationships between climatological CO2 partial pressure in surface seawater (pCO2SW) and sea surface temperature (SST), along with interannual changes in SST and wind speed. These optimum subannual relationships show significantly better correlation between pCO2SW and SST than the previous relationships using fixed monthly boundaries. Our diagnostic model yields an interannual variability of ±0.14 PgC yr−1 (1σ) with a 26-year mean of −1.48 PgC yr−1. The greatest interannual variability is found in the Equatorial Pacific, and significant variability is also found at northern and southern high-latitudes, depending in part, on which wind product is used. We provide an assessment of our approach by applying it to pCO2SW and SST output from a prognostic global biogeochemical ocean model. Our diagnostic approach applied to this model output shows reasonable agreement with the prognostic model net sea–air CO2 fluxes in terms of magnitude and phase of variability, suggesting that our diagnostic approach can capture much of the observed variability on regional to global scale. A notable exception is that our approach shows significantly less variability than the prognostic model in the Southern Ocean.