Clinical scenarios associated with low therapeutic effectiveness (LTE) are especially complex and highly relevant in oncology. The objective was to test a methodological framework for creating consensual clinical recommendations for routine practice. The study was in three phases from Mars 2006 to January 2008: 1) Definition of LTE situations; 2) Preparation by 10 experts of a panel of LTE situations in cancers of breast, lung, head and neck, colon and rectum and brain; and 3) Development of a consensus on each situation and its optimal treatment by gathering agreement and disagreements (two-round Delphi method) from 68 practicing oncologists in Andalusian Community. Three major and three minor criteria were established for an LTE situation, defined when at least one major or two minor criteria were met. The expert group proposed 48 possible LTE clinical scenarios for breast (n = 7), lung (10), brain (11), head and neck (11) and colorectal cancers (9). Sixty-eight oncologists agreed to participate in the study; the response rate was 79% (from 34 medical and 17 radiation oncologists) In the first round (definition), maximum agreement was obtained with the LTE definition of 10 of the 48 scenarios; in the second round (treatment options), maximum agreement was obtained on the treatment of 3 of these 10 scenarios. Oncologists reached low levels of agreement on the definition of an LTE situation and on its treatment recommendations. This study proposes an approach to the improvement of cancer management in situations of high uncertainty.