ObjectiveTo study the association of genes involved in the mitochondrial respiratory chain (MRC) pathway with body mass index (BMI) and obesity risk.DesignThis work studies three cross-sectional populations from Spain, representing three provinces: HORTEGA (Valladolid, Northwest/Centre), SEGOVIA (Segovia, Northwest/centre) and PIZARRA (Malaga,South).SettingForty-eight single nucleotide polymorphisms (SNPs) from MRC genes were selected and genotyped by SNPlex method. Association studies with BMI and obesity risk were performed for each population. These associations were then verified by analysis of the studied population as a whole (3731 samples).ParticipantsA total of 3731 Caucasian individuals: 1502 samples from HORTEGA, 988 from PIZARRA and 1241 from SEGOVIA.Resultsrs4600063 (SDHC), rs11205591 (NDUFS5) and rs10891319 (SDHD) SNPs were associated with BMI and obesity risk (p values for BMI were 0.04, 0.0011 and 0.0004, respectively, and for obesity risk, 0.0072, 0.039 and 0.0038). However, associations between rs4600063 and BMI and between these three SNPs and obesity risk are not significant if Bonferroni correction is considered. In addition, rs11205591 and rs10891319 polymorphisms showed an additive interaction with BMI and obesity risk.ConclusionsSeveral polymorphisms from genes coding MRC proteins may be involved in BMI variability and could be related to the risk to become obese in the Spanish general population.