Chronic non-communicable diseases (NCDs), are the leading causes of death among adults worldwide. It is projected that half of the NCDs could be avoided by preventing measures. Under the prospective epidemiological research studies in Iran (PERSIAN), we established a prospective population-based cohort study in southern Iran. The present study was designed to observe changing pattern of lifestyle transition over time and investigate the incidence and prevalence of regional modifiable risk factors as well as their associations with major NCDs. At baseline, 4063 participants aged 35-70 years were recruited on Oct, 2016and planned to get re-evaluated every 5 years along with annual follow-up. Data using validated electronic questionnaire comprising 55 questions and 482 items including general, medical and nutrition queries was collected. Blood, hair, nails, urine specimens and anthropometric measurements were taken. The response rate was 99%. In the results; male and female participants were 42.5% and 57.5%, respectively. Of note, 30.4% of women and 16.1% of men were obese. The prevalence of hypertension in men and women was 14.6% and 21%; however, diabetic men and women were 17.4% and 12.4%, respectively. Living in rural areas increased the odds of having hypertension by 1.33 (AOR = 1.33, 95% CI:1-09, 1.61). Noteworthy, logistic regression displayed that aging could predispose individuals to be more overweight, hypertensive and diabetic. The prevalence of multimorbidity of 3 or more NCDs were 8% (No. 326) and 6% (No.240), respectively. Intake of fruits, vegetables and dairy was less than two servings per day in 9.2%, 13% and 58.3% of the participants. Lower cardiovascular diseases and serum level of FBS and higher HDL level in sailors/fishermen compared to other job groups were significant (p-value <0.001). The second annual follow-up was completed and now at the end of the third wave. Findings of the present study signified the high prevalence of behavioral risk factors and their associations with respective NCDs. Subsequently, it is essential to keep track lifestyle variations, the modifiable risk factors and NCDs trends by prospective population-based cohort studies.