Purpose Recent data suggest that chronic low-grade inflammation, a characteristic of obesity, is associated with altered tryptophan (Trp) and tyrosine (Tyr) metabolism and plays a role in neuropsychiatric symptoms. The present study assessed the effect of an extreme short-term diet on Trp breakdown and inflammatory biomarkers in overweight adults. Methods Thirty-eight overweight participants (16 women, 22 men; average body mass index: 29 kg/m(2), mean age 52.8 years) were randomized into two diet groups: a very low kcal diet group (VLCD; empty set 600 kcal/day, n = 21) and a low kcal diet group (LCD; empty set 1,200 kcal/day, n = 17). Assays included the measurement of Trp, kynurenine (Kyn), and their ratio, neopterin, phenylalanine (Phe), Tyr, as biologic markers; leptin, plasma insulin, glucose, and homeostatic model assessment-insulin resistance; and interleukin 6, tumor necrosis factor alpha, and C-reactive protein, as biochemical and inflammatory markers at baseline and after 2 weeks of treatment. Results Weight loss diet lowered leptin levels in both groups by 46 %, although not reaching significance. Trp and Kyn decreased significantly by 21 and 16 % for VLCD and by 15 and 17 % for the LCD group, respectively. A significant reduction in Phe was only seen after VLCD. Inflammatory biomarkers, neopterin, and Tyr were not significantly altered during the study period. Leptin was significantly correlated with Trp breakdown before and after the intervention (P < 0.02). Conclusions Since disturbed metabolism of Trp affects biosynthesis of serotonin and might be associated with increased susceptibility for mood disturbances and carbohydrate craving, strategies to supplement Trp while dieting could be highly useful in treating uncontrolled weight gain or in preventing neuropsychiatric symptoms.