BACKGROUND: Adult GH deficiency (GHD) is associated with increased cardiovascular mortality. Recombinant human GH (rhGH) replacement has beneficial short-term metabolic effects. Although these positive effects sustain during longer follow-up, the prevalence of the metabolic syndrome (MS) remains increased in comparison with population data not adjusted for the higher mean BMI in GHD adults. OBJECTIVE: To explore whether middle-aged patients with proposed physiological rhGH replacement have been normalized with respect to MS and its individual components in comparison with the general population, adjusted for age, sex, and BMI. METHODS: One hundred and sixty-one GHD patients (aged 40-70 years) were studied before the start and after 5 years of rhGH replacement, and were compared with 1671 subjects (aged 45-66 years) from the general population (NEO Study). RESULTS: MS PROPORTION IN GHD PATIENTS WAS 41.0% BEFORE THE START OF RHGH SUPPLETION, INCREASING TO 53.4% AFTER 5 YEARS (P=0.007). DESPITE CHRONIC RHGH REPLACEMENT, GHD PATIENTS HAD A 1.3-TIMES HIGHER MS PROPORTION THAN THE GENERAL POPULATION, INDEPENDENTLY OF AGE, SEX, AND BMI (95% CI 1.11.5, P=0.008). THE GHD POPULATION SHOWED A DIFFERENT METABOLIC PROFILE THAN THE GENERAL POPULATION WITH SIMILAR BMI: an increased risk of hypertriglyceridemia (adjusted prevalence ratio (PR) 2.0, 95% CI 1.7-2.3) and low HDL-C (adjusted PR 1.8, 95% CI 1.5-2.2), but less hyperglycemia (adjusted PR 0.5, 95% CI 0.4-0.7). CONCLUSIONS: Despite 5 years of rhGH replacement, GHD patients still have a different metabolic profile and more frequently MS than the general population. These differences were independent of BMI, and resemble the unfavorable metabolic profile of untreated GHD patients, pointing to question the long-term benefits of rhGH replacement.