Appropriate interventions might improve the prevention of essential hypertension. This requires a comprehensive view of modifiable lifestyle factors (MLFs) distribution and effect. To determine how six MLFs (general adiposity, abdominal adiposity, alcohol consumption, smoking, diet, physical inactivity) for risk of hypertension are distributed and how their combinations affect the risk, a prospective study cohort of 11,923 healthy participants from the population-based European Prospective Investigation into Cancer and Nutrition (EPIC)–Potsdam Study was used. Of these, 1,635 developed hypertension during a mean follow-up of 10.3 years. Mutually exclusive combinations, clustering and interactions of MLFs were then investigated stratifying by sex, Hazard Ratios (HRs) and Population Attributable Risks (PARs%) were calculated. General adiposity alone was sufficient to increase the risk of hypertension (HR = 1.86, PAR% 3.36), and in this cohort it played a major role in enhancing the risk of hypertension, together with smoking and physical inactivity. MLFs had a different impact and a different modulation of risk in women and men, and they showed a remarkable tendency to occur in specific patterns with higher prevalence than expected. This indication can help to promote a holistic approach through multifactorial preventive strategies addressing more than a factor at a time. For prevention of hypertension addressing adiposity together with smoking, promoting at the same time physical activity should be the first choice.