Background: Transmission of HIV-1 with drug resistance mutations (DRMs) in Spain remains stable around 13%. However, the profile of recent HIV-1 seroconverters has experienced significant changes. Methods: Retrospective analyses of all individuals with HIV-1 infection acquired within the past 12 months recruited at a national registry since year 1997. Results: A total of 1032 recent HIV-1 seroconverters were examined (92.2% men; median age 31 years; 84% homosexual men). At the moment of diagnosis, median plasma HIV-RNA and CD4+ cell counts were 4.5 log copies/ml and 558 cells/ml, respectively. A total of 136 individuals (13.8%) carried non-B subtypes. Major primary DRMs were found in 13.4%, being 7.7% for nucleoside reverse transcriptase inhibitor (NRTI), 5.8% for nonnucleoside reverse transcriptase inhibitor (NNRTI) and 2.9% for protease inhibitor. NRTIDRMsignificantly declined from 23.7% in 1997-2000 to 5.7% in 2010-2012 (P<0.01). Overall, X4 viruses were found in 19.7% of HIV-1 seroconverters, increasing from 11.5% before 2001 to 23.3% since year 2010 (P=0.04). Interestingly, median CD4+ cell counts were significantly lower in seroconverters diagnosed during the last period after adjusting for potential confounders. In multivariate analyses, X4 tropism, high HIV-RNA, foreigners and non-B subtypes were independent predictors of lower CD4+ cell counts. Conclusion: Transmission of NRTI DRM has declined significantly in recent HIV-1 seroconverters in Spain. Conversely, X4 tropic viruses are on the rise and currently account for 23.3% of new HIV-1 infections. These individuals present with lower CD4+ cell counts suggesting that circulating HIV-1 strains might have gained virulence. © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins.