OBJECTIVES: Initial medication adherence, filling pharmacy scripts when first prescribed to begin a regimen, is an important yet understudied area. Long-term outcomes for chronically ill patients are dependent upon this critical early treatment phase. Recognizing how research findings can inform subsequent translation into effective clinical practices, this study summarizes the current literature on behavioral and psychosocial risk factors affecting initial medication adherence. METHODS: An international working group conducted a comprehensive systematic review utilizing multiple search terms for patient, provider or organizational factors associated with initial adherence. Following rigorous efforts limiting inclusion to studies targeting initial adherence versus broader or more ambiguous early treatment periods, we reviewed publications presenting primary data from 1966-2012. Eligible articles were abstracted documenting terminology, methodological approaches, and factors associated with adherence problems. We noted the frequency that unique risk factors were analyzed and their relative effect sizes calculated by the study authors.  RESULTS: Only 24 publications met eligibility criteria from 865 potentially relevant publications. The diverse papers covered an array of study designs, anaytic techniques, and populations (7 countries, sample sizes 60 – 5.2 million), utilizing administrative datasets and self-reported surveys. Several articles modelled numerous risk factors yet others focused on single variables. The most prevalent factor (n=16) was specific medication or drug class (OR range 1.50 – 4.87), followed by 14 papers reporting comorbodities or illness severity (ORs 1.40 – 2.78); 11 articles noted medication cost effects (ORs 1.20 – 7.30). Less frequently cited were socioeconomic status, physician characteristics or medication beliefs, factors magnifying adherence problems up to six-times. CONCLUSIONS: Attention to critical influences upon adherence during the initial treatment course is imperative to improving outcomes. Evolving research efforts into associations between initial adherence and numerous risk factors can highlight contributions towards beneficial interventions. Multidisciplinary approaches, particularly those tailored to specific risks and patient preferences, may help reconcile potential barriers while establishing positive longitudinal medication behavior.