This paper develops the methodological principles of pooled analysis design, using it to study situations of vulnerability among drug users at a regional level. Data from thirteen cross-sectional studies carried out in Argentina, Brazil and Uruguay between 1998 and 2004 were integrated. A critical review of the concept of data matrix which identifies four structural components, allowed us to: define the units of analysis spanning the different original populations; identify a core of common variables (social and demographic characteristics, drug use, sexual practices, serology of blood-borne and sexually transmitted diseases) with their respective values; examine the indicators, dimensions and procedures used to measure the variables; and establish their compatibility with a thematic and comparative analysis of data collection tools. The main result was a new data matrix with 3,534 cases. Multidisciplinary collaboration between teams and institutions from the three countries made it possible to maximize the available sources in order to analyze characteristics of the local contexts and of the overall regional.