OBJECTIVE To determine the minimal important difference in the frequency and severity of hot flashes that postmenopausal women desire from a nonhormonal agent. METHODS Women recorded their number of hot flashes daily, along with their degree of severity, using a diary for 1 week and completed the Menopause-Specific Quality of Life Questionnaire. Women were asked to report the percentage reduction in hot flashes that they would find clinically important. Distribution-based estimates were used to estimate the minimal important difference. RESULTS Approximately 69% of the postmenopausal women who reported their hot flashes as moderate to severe responded that they wanted a nonhormonal agent that provided at least a 50% mean reduction in the frequency of hot flashes (95% CI, 32% to 66%). Median hot flash reduction for all respondents was 50%. CONCLUSIONS The minimal clinically important difference in hot flashes is approximately 50%. This estimate can provide the basis to calculate sample size in clinical trials of anti-hot flash agents and in selecting possible candidates for investigation.