Background: Interruption of vector-borne transmission of Trypanosoma cruzi remains an unrealized objective in many Latin American countries. The task of vector control is complicated by the emergence of vector insects in urban areas.Methods: Utilizing data from a large-scale vector control program in Arequipa, Peru, we explored the spatial patterns of infestation by Triatoma infestans in an urban and peri-urban landscape. Multilevel logistic regression was utilized to assess the associations between household infestation and household- and locality-level socio-environmental measures.Results: Of 37,229 households inspected for infestation, 6,982 (18.8%; 95% CI: 18.4 - 19.2%) were infested by T. infestans. Eighty clusters of infestation were identified, ranging in area from 0.1 to 68.7 hectares and containing as few as one and as many as 1,139 infested households. Spatial dependence between infested households was significant at distances up to 2,000 meters. Household T. infestans infestation was associated with household- and locality-level factors, including housing density, elevation, land surface temperature, and locality type.Conclusions: High levels of T. infestans infestation, characterized by spatial heterogeneity, were found across extensive urban and peri-urban areas prior to vector control. Several environmental and social factors, which may directly or indirectly influence the biology and behavior of T. infestans, were associated with infestation. Spatial clustering of infestation in the urban context may both challenge and inform surveillance and control of vector reemergence after insecticide intervention. © 2013 Delgado et al.; licensee BioMed Central Ltd.