The transmission of drug-resistant HIV-1 (primary HIV resistance) is a cause of growing concern. The prevalence of drug-resistant variants in patients with primary HIV-1 infection (PHI) ranges from 10 to 36%. Unlike patients with secondary resistance, patients with primary HIV resistance do not show a rapid conversion to wild-type drug-sensitive virus in the absence of treatment. Moreover, primary HIV-1 resistance is associated with higher rates of treatment failure. Rapid diagnosis is important, since early events in PHI may have a critical role in disease progression. An early diagnosis is also essential to prevent HIV-1 transmission during the high viremic phase of PHI. This review focuses on prevalence, basic principles, diagnostic markers, and approaches for the treatment of PHI due to sexual transmission of drug-resistant HIV-1. The aim of the paper is to help clinicians to deal with patients presenting a PHI due to drug-resistant variants.