Development of evidence-based clinical practice guidelines has emphasized treatment efficacy under methodologically rigorous conditions; internal validity (i.e., efficacy) has been assessed well. Despite their experimental foundations, guidelines originally were considered physician education tools relevant to singular, idealized encounters. Now, in rushing to generalize, quantify, and regulate quality, guidelines are being applied to whole populations as quality review criteria. Clinical guidelines do not make operational how, or even make clear whether they should be so used. We studied the external validity, the generalizability and measurability for primary care, of a guideline for treatment of systolic heart failure. Patient and clinical factors reducing generalizability were examined. Imprecise definition and reliance on single measures of recommendations were studied as limits to measurability. Patient, physician, organizational, and system factors influenced guideline validity. Attention to myriad invalidity sources undermining implementation and evaluation of efforts to improve quality and outcomes of primary care is critical.