John Ioannidis has worked in the fields of evidence-based medicine, clinical investigation, clinical and molecular epidemiology, clinical research methodology, empirical research methods, statistics, and genomics. He has a strong interest in large-scale evidence (in particular randomized trials and meta-analyses) and in appraisal and control of diverse biases in biomedical research. He is interested in developing and applying new research methods, and in the interdisciplinary enhancement of existing research methods for study design and analysis in biomedicine. 

Some of Ioannidis' most influential papers in terms of citations are those addressing issues of replication validity of genetic association studies, biases in biomedical research, research synthesis methods, extensions of meta-analysis, genome-wide association studies and agnostic evaluation of associations, and validity of randomized trials and observational research. He has also designed, steered and participated in influential randomized trials (in particular, the major trials that changed decisively the management and outcome of HIV infection, but also trials in nephrology, and in antibiotic use in the community), and large international consortia that have helped transform the efficiency of research in diverse fields of genomic, molecular and clinical epidemiology.