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Background: Candida.albicans, as an opportunistic pathogen, can cause superficial and life-threatening candidiasis in immunocompromised individuals.The formation of surface-associated biofilms and the appearance of drug resistance pose a significant challenge for clinical intervention.Methodology/Principal Findings: A total of 104 hospital-acquired C.alibcans clinical isolates collected from sterile sites and mucosal lesions of 92 infectious disease patients (viral hepatitis, tuberculosis and AIDS) in Shanghai Public Health Clinical Center (Shanghai, China) were analyzed.The resistance rate to fluconazole, itraconazole and itraconazole were 12.5%, 15.4% and 10.6% respectively.Multilocus sequence typing (MLST) analysis identified 63 diploid sequence types (DSTs) with a decentralized phylogeny, of which 41 DSTs (65.1%) had not been reported in the online MLST database.Loss of heterozygosity was typically observed in ACC 1 and ADP1 sequences obtained from six sequential isolates from a patient receiving anti-fungal treatment, which exemplified the effect of microevolution on C.albicans genetic alterations.The biofilm formation capability, an important virulence trait of C.albicans, was highly variable among strains isolated from different anatomical sites (p=0.0403) and significantly affected by genotypes (p=0.0185).The elevated mRNA level of the azole antifungal target ERG11 gene and efflux pump genes (CDR1, CDR2, and MDR1) were detected in 9%-18% of azole-resistant and susceptible-dose dependent (S-DD) isolates.Twelve mutations encoding distinct amino acid substitutions in ERG11 were found in azole-resistant and S-DD isolates.Among them, A114S, Y132H and Y257H substitution in the ERG11 gene may be primarily related to azole resistance.Conclusions/Significance: Our observation suggests that multiple inter-related underlying mechanisms, including genetic and environmental adaptations etc, account for high surface adhesion or azole resistance in clinical C.albicans infection.