A comparative analysis of three different estimation methods of cocaine use in Milan, Italy, is carried out, including an analysis of the size and trends of the underlying reference population. The three cocaine use estimates are derived from wastewater analysis, a “street” survey and one-source capture-recapture analysis of administrative sanctions for drug possession. All three data sources span several years during the decade 2000-2010. For each method, assumptions and limitations are discussed. It is concluded, although the amount of data regarding cocaine use in Milan during the years 2000-2010 is considerable, that none of the estimates is completely reliable, mainly because of the many assumptions needed for inference to the whole community, that all three estimates however agree on a substantial reduction in cocaine use and users between the years 2007 and 2010. The recently developed wastewater analysis technique yields estimates comparable to those derived from the street based survey, while capture-recapture analysis of administrative data on identification by law enforcement agencies as cocaine user probably targets only a subpopulation of all users.