The mutational spectrum of the phenylalanine hydroxylase gene (PAH) in Mexico is unknown, although it has been suggested that PKU variants could have a differential geographical distribution. Genotype–phenotype correlations and genotype‐based predictions of responsiveness to tetrahydrobiopterin (BH₄) have never been performed. We sequenced the PAH gene and determined the geographic origin of each allele, mini‐haplotype associated, genotype–phenotype correlations and genotype‐based prediction of BH₄ responsiveness in 48 Mexican patients. The mutational spectrum included 34 variants with c.60+5G>T being the most frequent (20.8%) and linked to haplotype 4.3 possibly because of a founder effect and/or genetic drift. Two new variants were found c.1A>T and c.969+6T>C. The genotype–phenotype correlation was concordant in 70.8%. The genotype‐based prediction to BH₄‐responsiveness was 41.7%, this information could be useful for the rational selection of candidates for BH₄ testing and therapy.