Circulating cell-free microRNAs (cfmiRNA) are an emerging class of biomarkers that have shown great promise in the clinical diagnosis, treatment, and monitoring of several pathological conditions, including cancer. However, validation and clinical implementation of cfmiRNA biomarkers has been hindered by the variability introduced during different or suboptimal specimen collection and handling practices. To address the need for standardization and evidence-based guidance, the National Cancer Institute (NCI) developed a new Biospecimen Evidenced-Based Practices (BEBP) document, entitled "Cell-free miRNA (cfmiRNA): Blood Collection and Processing". The BEBP, the fourth in the document series, contains step-by-step procedural guidelines on blood collection, processing, storage, extraction, and quality assessment that are tailored specifically for cfmiRNA analysis of plasma and serum. The workflow outlined in the BEBP is based on the available literature and recommendations of an expert panel. The BEBP contains the level of detail required for development of evidence-based standard operating procedures (SOPs) as well as the flexibility needed to accomodate (i) discovery- and inquiry-based studies and (ii) the different constraints faced by research labs, industry, clinical and academic institutions to foster widespread implementation. Guidance from the expert panel also included recommendations on study design, validating changes in workflow, and suggested quality thresholds to delineate meaningful changes in cfmiRNA levels. The NCI cfmiRNA: Blood Collection and Processing BEBP is available here as supplementary information as well as through the NCI Biorepositories and Biospecimen Research Branch (BBRB) (https://biospecimens.cancer.gov/resources/bebp.asp).