Cryptosporidium infection is commonly observed among children and the immune compromised in developing countries, but large-scale outbreaks of disease among adults have not been reported. In contrast, outbreaks of cryptosporidiosis in the US and Canada are increasingly common among patients of all ages. Thus, it seems likely that residents of highly endemic regions acquire some level of immunity while residents of the developed world do not. A new immunodominant Cryptosporidium parvum antigen in the 15/17-kDa size range was identified as the 60S acidic ribosomal protein P2 (CpP2). We developed a recombinant protein-based ELISA for serologic antibody population surveillance that was 89% sensitive and 92% specific relative to the large format Western blot. The human IgG response is directed almost exclusively towards the highly-conserved, carboxy-terminal 15 amino acids of the protein. Although IgG antibody cross reactivity was documented using sera from acute babesiosis patients, the development of an anti-CpP2 antibody response in our Peru study population correlated better with Cryptosporidium infection than with infection by any other parasitic protozoan. In Haiti, antibody prevalence to the CpP2 protein plateaus at 11-20 years of age. Because anti-CpP2 IgG antibodies were only found among residents of developing world countries where Cryptosporidium infection occurs early and often, we propose that this response may be a proxy for the intensity of infection and for acquired immunity.