Twenty-nine HIV-1 recently infected subjects were retrospectively studied to investigate both the prevalence of nucleoside reverse transcriptase inhibitors (NRTI)-related mutations at primary infection and the proportion of naturally occurring mutations in protease inhibitor (PI)-naive patients. Neither HIV-1 plasma viremia nor CD4 absolute count at baseline could distinguish patients with NRTI pre-existing mutations from those with wild-type virus. An increasing proportion of ZDV-related mutations was observed over time with an overall frequency of 20.7% in the study period. Only 1 out of 6 patients (16.7%) with ZDV-related mutations showed a phenotypically ZDV resistant isolate. A striking proportion of polymorphic changes was present in the protease region of pol gene in newly infected individuals. As many as 80% of seroconverters presented at least one naturally occurring substitution. Some PI-associated substitutions, thought to be compensatory in protease enzymatic function, could confer intermediate to high PI-resistance. Their role following PI administration remains to be elucidated. Our data suggest that the choice of drugs should be oriented by both genotypic and phenotypic evaluations to tailor individual regimens in seroconverters.