We compare space-based measurements of carbon monoxide (CO) during April 1994 and October 1984 and 1994 from the early MAPS instrument with those during 2000–2004 from the MOPITT instrument. We show that a three-dimensional global composition model can be used to account for differences in retrieval sensitivity between the two instruments and between the different years of MOPITT data. This allows direct comparison of CO amounts over most of the globe at different times. These types of changes in short-lived constituents cannot be assessed with local measurements. Though the existing space-based data are too sparse both temporally and geographically to allow trend estimates, we find substantial variations in midtropospheric CO between the different years in many continental-scale regions. During April, average CO is ∼12–18 ppbv (∼10–20%) greater during 2000–2004 than during 1994 over North America, southeast Asia and North Africa though the global mean value is nearly the same. During October 1994, observations show CO enhancements of 15–20 ppbv relative to 1984 or 2000–2004 over South America and a similar, though slightly smaller (9–19 ppbv), enhancement globally. Southeast Asia, Europe and North America all show similar October CO levels in 1994 and 2000–2004, with both times showing substantially more pollution (13–29 ppbv) than 1984. Variations over Europe and Africa are consistent in both seasons, while changes elsewhere are not. Changes over southeast Asia and North Africa are substantially in excess of interannual variability, while those over North and South America and southern Africa are only marginally so. Model sensitivity studies examining the response to changes in emissions indicate probable causes of the CO changes over different regions. Over southeast Asia and North America, CO is most sensitive to industrial and biomass burning emissions, implying that changes in these sources likely account for the 13–29 ppbv increases seen there between 2000–2004 and earlier years. Over North Africa, CO is strongly influenced by numerous sources as well as meteorology, precluding attribution of increases to particular factors. Over South America and southern Africa, variations in both biomass burning and isoprene emissions likely contributed to the ∼10–20 ppbv changes.