The adipocytokines, leptin, adiponectin, and interleukin-6, which stimulate liver C-reactive protein (CRP) production, are regarded as potential candidate intermediates between adipose tissue and overweight-induced hypertension. We examined the associations between leptin, adiponectin, and CRP levels with both prevalent and 5-year incident hypertension (IHT) in a general population of Danish adults (n = 5,868, 51.3% women, mean age 45.8 ± 7.9 years). We recorded 2195 prevalent and 379 incident cases of hypertension. In models including leptin, CRP, adiponectin, sex, age, lifestyle risk factors, lipids, insulin, hemoglobin A1c, and in the incident model also baseline heart rate and blood pressure, only leptin of the three candidate intermediates was significantly associated with both prevalent and IHT [odds ratio (OR) = 1.18, 95% confidence interval (CI) 1.06-1.32, P = 0.002, and OR = 1.24, 95% CI 1.01-1.54, P = 0.044] for one standard deviation increase in log-transformed leptin levels, respectively. Log-transformed CRP was associated with prevalent (OR = 1.16, 95% CI 1.07-1.26, P < 0.001) but not IHT (OR = 0.98, 95% CI 0.84-1.14, P = 0.76). Log-transformed adiponectin was neither associated with prevalent nor IHT (OR = 0.94, 95% CI 0.87-1.02, P = 0.11 and OR = 0.93, 95% CI 0.80-1.08, P = 0.33). Comparing the lowest with the highest quintile of sex-specific BMI levels, there was an almost two-fold increase in IHT (OR = 1.89, 95% CI 1.10-3.25, P = 0.023) in the fully adjusted model. The population attributable risk estimate of IHT owing to overweight was 31%. Leptin, but not adiponectin or CRP, may play a mediating role in overweight-induced hypertension. However, as BMI was a strong independent predictor of hypertension, other factors than leptin must be involved in the pathogenesis of overweight-related hypertension.