We have recently demonstrated that the CCR5Delta32 protein interacts with CCR5 and CXCR4 and down-modulates their cell surface expression. We have also reported the absence of detectable expression of the truncated CCR5Delta32 protein in four out of six human immunodeficiency virus-infected (HIV(+)) CCR5(-/-) individuals. To explain the defect in protein expression in these samples, we cloned and sequenced the promoter regions of the six HIV(+) individuals. We have identified several polymorphisms in the CCR5Delta32 promoter region, but these polymorphisms were not associated with significant differences in mRNA levels. Coupled in vitro transcription/translation and polyribosome analysis demonstrated a strong association between a variant genotype designated CCR5Delta32 59537-A/A and a low translation efficiency. Protein analysis indicated that the peripheral blood mononuclear cells from two of the HIV(+) CCR5(-/-) individuals carrying the CCR5Delta32 59537-A/A variant expressed trace amounts of CCR5Delta32 protein compared to the individuals carrying the CCR5Delta32 59537-G/G genotype. The results imply that the absence of CCR5Delta32 protein in two HIV(+) individuals is due to a genetic defect in the translation of the protein. Together, these results highlight the importance of the CCR5Delta32 protein as an HIV suppressive factor and provide further insight into the mechanism of the protective effect of the CCR5Delta32 mutation.