Background Breastfed children absorb persistent and toxic chemicals such as organohalogen compounds (OHCs) during the entire lactation period. Nursing is a main contributor to the burden of these pollutants in the first years of life, hence further assessments on the OHC load processes are needed. Objectives To identify the determinants of OHC increase in children at four years of age, considering concentration gains, maternal venous concentrations and breastfeeding time. Methods Concentrations of 19 organochlorine compounds (OCs) and 14 polybrominated diphenyl ethers (PBDEs) were analyzed in maternal venous (n = 466), cord blood (n = 326) and children venous serum at four years of age (n = 272) in the Asturias INMA cohort representing the Spanish general population. Data were evaluated considering the socio-demographic and individual information collected at recruitment and follow up surveys, as well as the OHC physical-chemical constants. Results The four years-old children concentration gains of the most abundant OHCs showed strong correlations (R2 = 0.65–0.93) with the maternal concentrations during pregnancy and lactation period. The child gain/maternal transfer rates of most correlated pollutants were similar. Discussion Between 65 and 93% of the variance of OCs in four years-old children was explained by the maternal concentrations during pregnancy and the lactation period. The compounds with log(Kow) > 3.7 (hydrophobic) showed analogous child gain/maternal transfer rates indicating similar processes of membrane lipid dissolution and passive diffusion from the epithelial cells into the milk. Molecular weight of these pollutants did not influence on these rates. Compounds with low log(Koa) such as hexachlorobenzene are more volatile and less retained, involving lower child gain/maternal transfer rates. These results may be useful to anticipate the increase of the concentrations of OCs in children using the maternal concentration of these compounds during pregnancy and the planned lactation period and to implement prophylactic measures in mothers with high venous pollutant concentrations.