There is evidence for a link between MHC and squamous cell carcinoma of the cervix (SCCC), and different patterns of association in different patient cohorts have been reported. To investigate this subject in the Spanish population, HLA class I, -II serotypings and HLA-DQB1 oligogenotypings of 142 patients and 138 healthy sex-age-matched controls were performed. Comparative analysis of the DR2-DQ3-stratified phenotypes demonstrated a strong association between DR2 and DQ3 in SCCC (Pc9 < 7 x 10(-8)). However, no interaction was observed between the two HLA factors, which seem to confer two weak and independent risks. Thus, phenotypes with DR2 and/or DQ3 (patients, 79%, controls, 60%; P < 5 x 10(-4)) were over-represented, while the less common DR2/DQ3-negative phenotypes with the HLA class I A2 antigen were found to confer the highest risk (EF = 62%, Pc84 < 1 x 10(-2)) of SCCC. Comparative analysis of allele frequencies revealed two weakly significant increases, one for DQB1*0301 (P < 1 x 10(-2)) in low-moderate dysplasias (CINI,II), and the other for DQB1*0402 (P < 3 x 10(-2)) in severe dysplasia in situ (CINIII/CIS), and a trend for an increase of DQB1*0302 among CINIII/CIS and invasive SCCC (ISCCC). With regard to DQB1 genes encoding the DR2-associated DQ serotypes, there was no significant deviation in patients. In contrast, the frequency of DQB1*0603 was found to be weakly decreased in CINI,II (P < 5 x 10(-2)) and ISCCC (P < 3 x 10(-2)), indicating a protective effect for this DR13 serotype-associated allele. No significant association could be shown between HLA and HPV infective status. However, there is circumstantial evidence that HPV-infected lesions may have been misassigned in some cases, and the sample size was small, so a role for DQB alleles in modifying the course of HPV-induced diseases cannot be excluded. The observations in this study suggest A2, DR2, DQB1*0301, DQB1*0402 and DQB1*0603 as independent factors associated with SCCC and as relevant targets in HLA-restricted peptide presentation. Our results are consistent with the theory that HLA loci may have different contributions in susceptibility and resistance to low-moderate dysplasias, CIS and invasive SCCC.