Background Cysteine is a non-essential sulfur aminoacid, synthesized from methionine and homocysteine by the two sequential enzymes: cystathionine beta synthase (CBS) and cystathionase. Plasma total cysteine (tCys) concentrations are positively associated with body mass index (BMI) in the general population [1], but the direction of causality is unknown. Aim To investigate whether the association of tCys with BMI is mediated through body lean mass or fat mass, and to search the literature for underlying mechanisms. Methods The study included 5179 Norwegians (aged 46-73 y), recruited from the general population in the Hordaland Homocysteine Study [2], who underwent two assessments 6 y apart. Dual-energy X-ray absorptiometry was performed at follow-up. Linear regression models and concentration-response curves were used to investigate cross-sectional associations of tCys with lean mass and fat mass with adjustments for potential confounders. We also investigated associations of baseline tCys and change in tCys over 6 y with body composition at follow up Results tCys was not associated with lean mass, but showed a strong positive association with fat mass (partial r =0.25, P <0.001), with adjustment for age, sex and lean mass. tCys was the strongest plasma variable associated with fat mass, stronger than and independent of plasma lipids. Women in the highest tCys quintile had fat mass 6 kg greater than that of women in the lowest quintile (95% CI: 5, 7 kg), with adjustment for plasma lipids, physical activity, and dietary fat, protein, and total energy intakes. Corresponding values for men were 4 kg (95% CI: 3, 5 kg; P<0.001 for ANOVA across quintiles in both genders). A higher baseline tCys and a rise in tCys over 6 y were both associated with greater fat mass at follow-up (P<0.001 by linear regression), with no effect on lean mass. Discussion Literature evidence points to tCys as a powerful but ignored determinant of fat mass. Homocystinurics with genetic deficiency of CBS enzyme (and hence decreased cysteine synthesis) are thin and underweight [3], a feature not reported for other types of homocystinuria, in which cysteine synthesis is normal. In contrast, Down syndrome patients, having triple copies of the CBS gene and elevated tCys, are overweight. Dietary cysteine supplements enhance weight gain in cachectic AIDS and cancer patients [4]: an effect generally attributed to improved lean mass, but do we know? Dietary restriction of the cysteine-precursor methionine reduces visceral fat mass in rats [5]. Several early studies on rat adipocytes demonstrate potent antilipolytic and lipogenic actions of cysteine. Conclusions Overall, our data and literature evidence suggest that cysteine could be an important modulator of body fat mass in humans, and if so, provides an attractive anti-obesity target.