Abstract: Research with injection drug users (IDUs) benefits from interdisciplinary theoretical and methodological innovation because drug use is illegal, socially sanctioned and often hidden. Despite the increasing visibility of interdisciplinary, mixed methods research projects with IDUs, qualitative components are often subordinated to quantitative approaches and page restrictions in top addiction journals limit detailed reports of complex data collection and analysis logistics, thus minimizing the fuller scientific potential of genuine mixed methods. We present the methodological logistics and conceptual approaches of four mixed-methods research projects that our interdisciplinary team conducted in San Francisco with IDUs over the past two decades. These projects include combinations of participant-observation ethnography, in-depth qualitative interviewing, epidemiological surveys, photo-documentation, and geographic mapping. We adapted Greene et al.’s framework for combining methods in a single research project through: data triangulation, methodological complementarity, methodological initiation, and methodological expansion. We argue that: (1) flexible and self-reflexive methodological procedures allowed us to seize strategic opportunities to document unexpected and sometimes contradictory findings as they emerged to generate new research questions, (2) iteratively mixing methods increased the scope, reliability, and generalizability of our data, and (3) interdisciplinary collaboration contributed to a scientific “value added” that allowed for more robust theoretical and practical findings about drug use and risk-taking.