Comparisons of eddy covariance (EC) tower measurements of CO2 concentration with mid-tropospheric observations from the Atmospheric Infrared Sounder (AIRS) allow for evaluation of the rising global signal of this greenhouse gas in relation to surface carbon dynamics. Using an information theory approach combining relative entropy and wavelet multi-resolution analysis, this study has explored correlations and divergences between mid-tropospheric and surface CO2 concentrations in grasslands of northeastern Kansas. Results show that surface CO2 measurements at the Kansas Field Station (KFS) and the Konza Prairie Biological Stations 1B (KZU) and 4B (K4B) with different land-cover types correlate well with mid-tropospheric CO2 in this region at the 512-day timescale between 2007 and 2010. Relative entropy further reveals that AIRS observations are indicative of surface CO2 concentrations for all land-cover types on monthly (32-day) and longer timescales. AIRS observations are also similar to CO2 concentrations at shorter timescales at sites KFS and K4B experiencing woody encroachment, though these results require further investigation. Differences in species composition and microclimate add to the variability of surface concentrations compared with mid-tropospheric observations.