Objective: Dietary protein plays a role in counteracting age-related muscle loss. However, limited long-term data exist on protein intake and markers of cardiometabolic health, which tend to deteriorate with age. Design: Prospective cohort study. FFQ-derived protein intake (g/d) and cardiometabolic markers were assessed up to five times across 20 years. Markers included systolic (SBP) and diastolic (DBP) blood pressures, circulating lipids (total, HDL and LDL cholesterol; TAG), estimated glomerular filtration rate (eGFR), fasting glucose (FG), weight and waist circumference (WC). Mixed models accounting for repeated measures were used to estimate adjusted mean annualized changes in outcomes per quartile category of protein. Setting: Framingham Heart Study Offspring cohort, USA. Subjects: Participants (n 3066) with 12 333 unique observations, baseline (mean (sd)) age=54·0 (9·7) years, BMI=27·4 (4·9) kg/m2, 53·5 % female. Results: In fully adjusted models, there were favourable associations (mean (se)) of total protein with annualized changes in SBP (lowest v. highest intake: 0·34 (0·06) v. 0·04 (0·06) mmHg, P trend=0·001) and eGFR (−1·03 (0·06) v. −0·87 (0·05) ml/min per 1·73 m2, P trend=0·046), unfavourable associations with changes in FG (0·013 (0·004) v. 0·028 (0·004) mmol/l, P trend=0·004) and no associations with weight, WC, DBP or lipids. Animal protein was favourably associated with SBP and unfavourably with FG and WC; plant protein was favourably associated with FG and WC. Conclusions: The present study provides evidence that protein intake may influence changes in cardiometabolic health independent of change in weight in healthy adults and that protein’s role in cardiometabolic health may depend on the protein source.