Since the seminal observation that Greenland Eskimos have lower cardiovascular disease mortality than genetically related Danes, adequate intake of fish or the fatty acids unique to fish, eicosopentanoic acid (EPA, 20:5n-3) and docosexaenoic acid (DHA, 22:6n-3), have been recommended to decrease risk. Potential mechanisms for reduced cardiovascular risk included anti-inflammatory, anti-thrombotic, antihypertensive, hypo-triglyceridemic and antiarrhythmic properties. A large body of clinical research is available to address issues related to defining a potential association or a causative link between EPA and DHA intake and clinical cardiovascular outcomes. Nonetheless, the results of several dozen prospective cohort studies and randomized trials, and several systematic reviews and meta-analyses generated from this body of work are inconsistent. In a previous systematic review we provided a qualitative synthesis of evidence from prospective cohorts and RCTs on the relationship between fish consumption and EPA and DHA intakes with cardiovascular clinical outcomes. While there was evidence that higher consumption of fish was associated with favorable clinical outcomes in cohorts, the corresponding data on EPA and DHA intakes was equivocal. On the basis of available data others concluded that for daily intakes of (combined) EPA and DHA in excess of 0.30 to 0.50 grams, the impact of EPA and DHA on cardiovascular mortality reaches a plateau, and that this could explain the different conclusions based on the data from various cohorts, or cohorts and RCTs. From this perspective, and in analogy to observations from clinical medicine, prospective cohorts and RCTs offer complementary information on the association of interest, as they refer to different intake (dose) levels and periods of observations. We performed a systematic review and meta-analysis of evidence from prospective cohorts and RCTs on the relationship of EPA and DHA intakes with cardiovascular or all-cause mortality. Our aim was to assess the apparent congruence of these two types of study designs and to describe how randomized intervention trials and observational studies compare in their target populations, outcome definitions and results, with the intent to defining the dose-response relationships of EPA and DHA intakes to cardiovascular and all-cause mortality across diverse settings and wide ranges of intake levels.