OBJECTIVE. The mechanisms by which overweight and physical inactivity lead to hypertension are complex. Leptin, an adipocyte-derived hormone, has been linked with hypertension. We wanted to investigate the relationship between leptin, physical activity and new-onset hypertension. METHODS. The study was a prospective cohort study of 744 women and 367 men, who were normotensive in the third Copenhagen City Heart Study (CCHS) examination, performed 1991−94. Based on questionnaire items, the participants were divided into two groups with low (n = 674) and high (n = 437) levels of leisure-time physical activity, respectively. RESULTS. Between the third and the fourth CCHS examination, performed 2001?03, 304 had developed hypertension, defined as systolic blood pressure (SBP) ≥140 mmHg or diastolic blood pressure (DBP) ≥90 mmHg or use of antihypertensive medication. In a logistic regression model, including age, sex, body mass index, SBP, DBP, level of physical activity and leptin, we found a significant interaction between leptin and level of physical activity with new-onset hypertension as outcome variable (p = 0.012). When we entered the interaction variables, effect of leptin with low level of physical activity and with high level of physical activity, respectively, in the original model, leptin predicted new-onset hypertension in participants with low level of physical activity [odds ratio (95% confidence interval): 1.16 (1.01−1.33) for one unit increase in log-transformed leptin levels, p = 0.038], but not in participants with high level of physical activity [0.88 (0.74−1.05), p = 0.15]. CONCLUSION. We found that leptin predicted new-onset hypertension but only in participants with low level of physical activity.