Pathogenicity mechanisms of the yeast Candida albicans involve filamentous growth, adhesion, invasion, and toxin production. Interestingly, clinical isolates, and other Candida spp., can cause infection independent of filamentation or toxin production. These strains and species often are characterized as avirulent ex vivo, yet this does not correlate with their potential to cause infection. We hypothesized that specific host factors, which trigger pathogenicity in vivo, are absent in in vitro infection models and thereby clinical isolates can seem avirulent ex vivo. We investigated how albumin, the most abundant protein in humans, impacts infection and cytotoxic potential of C. albicans in vitro. The presence of albumin induces otherwise non-damaging and non-filamentous clinical isolates to cause host cell cytotoxicity. Moreover, avirulent deletion mutants deficient in filamentation, adhesion, or toxin production are restored in their cytotoxicity by albumin. This involves transcriptional and metabolic reprogramming of C. albicans, increasing biofilm formation and production of the oxylipin 13-hydroxyoctadecadienoic acid, driving host cell cytotoxicity. Collectively, our study uncoveres a pathogenicity mechanism by which C. albicans causes epithelial cytotoxicity independent of its conventional virulence mechanisms. This alternative pathogenicity strategy helps to explain the avirulence of clinical isolates ex vivo, when they are separated from the host environment.