Although ATP-binding cassette transporter A1 (ABCA1) is well known for its role in cholesterol efflux and HDL formation, it is expressed in various tissues, where it may have different functions. Because hypoalphalipoproteinemia is highly prevalent in Mexico, we screened the ABCA1 coding sequence in Mexican individuals with low and high HDL cholesterol levels to seek functional variants. A highly frequent nonsynonymous variant (R230C) was identified in low-HDL cholesterol but not in high-HDL cholesterol individuals (P = 0.00006). We thus assessed its frequency in the Mexican-Mestizo general population, seeking possible associations with several metabolic traits. R230C was screened in 429 Mexican Mestizos using Taqman assays, and it was found in 20.1% of these individuals. The variant was significantly associated not only with decreased HDL cholesterol and apolipoprotein A-I levels but also with obesity (odds ratio 2.527, P = 0.005), the metabolic syndrome (1.893, P = 0.0007), and type 2 diabetes (4.527, P = 0.003). All of these associations remained significant after adjusting for admixture (P = 0.011, P = 0.001, and P = 0.006, respectively). This is the first study reporting the association of an ABCA1 variant with obesity and obesity-related comorbidities as being epidemiologically relevant in the Mexican population.