The effect of elevated carbon dioxide (CO2) on crop yields is one of the most uncertain and influential parameters in models used to assess climate change impacts and adaptations. A primary reason for this uncertainty is the limited availability of experimental data on CO2 responses for crops grown under typical field conditions. However, because of historical variations in CO2, each year farmers throughout the world perform uncontrolled yield ‘experiments’ under different levels of CO2. In this study, measurements of atmospheric CO2 growth rates and crop yields for individual countries since 1961 were compared to empirically determine the average effect of a 1 ppm increase of CO2 on yields of rice, wheat, and maize. Because the gradual increase in CO2 is highly correlated with major changes in technology, management, and other yield controlling factors, we focused on first differences of CO2 and yield time series. Estimates of CO2 responses obtained from this approach were highly uncertain, reflecting the relatively small importance of year-to-year CO2 changes for yield variability. Combining estimates from the top 20 countries for each crop resulted in estimates with substantially less uncertainty than from any individual country. The results indicate that while current datasets cannot reliably constrain estimates beyond previous experimental studies, an empirical approach supported by large amounts of data may provide a potentially valuable and independent assessment of this critical model parameter. For example, analysis of reliable yield records from hundreds of individual, independent locations (as opposed to national scale yield records with poorly defined errors) may result in empirical estimates with useful levels of uncertainty to complement estimates from experimental studies.