The American College of Sports Medicine (ACSM) equation for estimating oxygen consumption (VO2) is often inappropriately applied to non-steady-state treadmill exercise. Therefore, it was the purpose of this investigation to develop an equation to estimate VO2 that could be applied to non-steady-state treadmill exercise in a population of patients with osteoarthritis of the knee, and to assess the generalizability of this equation for estimating VO2peak in patients with cardiovascular disease. Subjects for the investigation were 414 participants in the Fitness and Arthritis in Seniors Trial (FAST), and 362 patients with cardiovascular disease. Results from the FAST subjects showed that the ACSM equation was inappropriate for estimating VO2 during non-steady-state incremental treadmill walking. We developed the following equation (FAST) using speed and the interaction between speed and grade as the predictor variables during treadmill walking: VO2(ml.kg-1.min-1) = 0.0698 x speed(m.min-1) + 0.8147 x grade(%) x speed(m.min-1) + 7.533 ml.kg-1.min-1 The generalizability of the FAST equation for estimating VO2peak was evaluated in the patients with cardiovascular disease. The measured VO2peak of these patients was 23.7 +/- 0.3 ml.kg-1.min-1, whereas the VO2peak values estimated from the FAST equation and the ACSM equation were 24.1 +/- 0.3 and 33.2 +/- 0.5 ml.kg-1.min-1, respectively. No significant differences were found between the measured VO2peak and that estimated from the FAST equation. The VO2peak estimated from the ACSM equation was significantly greater than the measured VO2peak. These results suggest it is more appropriate to use the FAST equation rather than the ACSM equation to estimate VO2 in older patients with either osteoarthritis of the knee or cardiovascular disease.