Introduction: Current research suggests that Chios mastic (Pistacia lentiscus var. chia) possesses beneficial (antimicrobial, antioxidant, hepatoprotective) properties. This study aims to assess its effects on cardiologic and hepatic biochemical indices of human subjects. Materials and methods: Subjects (n = 133, aged over 50) were randomly assigned to two groups, the first (high-dose group) ingesting daily 5 g of mastic powder and the second receiving daily a Chios mastic solution (low-dose group). Serum biochemical parameters were determined on a monthly basis for an 18-month (high-dose group) and a 12-month (low-dose group) follow-up period. Generalized least squares random-effects linear regression was performed. Results: The group ingesting Chios mastic powder (high-dose group) exhibited a decrease in serum total cholesterol, LDL, total cholesterol/HDL ratio, lipoprotein (a), apolipoprotein A-1, apolipoprotein B (apoB/apoA-1 ratio did not change), SGOT, SGPT and gamma-GT levels; in the second (low-dose) group, glucose levels decreased in males. Discussion: Chios mastic powder could have a hepatoprotective/cardioprotective role in vivo in humans.