The CASS randomized trial was compared with the Veterans Administration (VA) randomized study of coronary bypass surgery with respect to the influence of clinical characteristics on the comparison of medical and surgical therapy. With regard to clinical baseline characteristics, the CASS population was overall at lower risk than the VA population. Average percent survival for years 1 through 6 were greater in the CASS than in the VA study for patients in both the medical and surgical groups. In the VA population, a multivariate risk index was developed with the use of presence or absence of New York Heart Association functional class III or IV, history of hypertension, history of myocardial infarction, and ST depression on the resting electrocardiogram. Low-, middle-, and high-risk terciles in the VA study population were determined based on this index. In the low-risk tercile, VA patients treated medically had a greater percent survival at 6 years than those treated surgically. In the high-risk tercile, VA patients treated surgically had markedly improved survival compared with those treated medically. These results were not replicated by the CASS study. In CASS, there were no significant differences between patients assigned to medical and surgical treatment within the terciles. Other noninvasive risk indexes were explored in CASS, but no subgroups defined solely by clinical features could be found wherein patients assigned to medical and surgical therapy were significantly different. Basic differences in the populations sampled are the most probable reason for the different results in the CASS and VA trials.