Clinical observations have long suggested that women are protected against paracoccidioidomycosis. 17β-estradiol, the main female estrogen, inhibits conidia-to-yeast transformation (C-to-Y), which is required for the infection establishment. However, experiments in murine models have yielded conflicting results, suggesting that C-to-Y inhibition, alone, fails to explain the female-associated protection and that sexual hormones may also act by modulating the host’s immune responses. Therefore, this issue remains unsolved. Strikingly, no studies have compared the severity of paracoccidioidomycosis between men and women. This retrospective case-control study compared 36 women with 72 age-matched men for clinical–demographic, laboratory, and chest imaging findings. Overall, paracoccidioidomycosis in women presented the main features described in the acute/subacute and chronic forms seen in men. Women also showed similar demographic features and clinical–laboratory and imaging severity scores as men. We additionally reviewed 58 paracoccidioidin skin test surveys undertaken by volunteers from endemic areas. Data accumulated from 10.873 tests showed that females and males are infected with similar magnitudes (21.9% vs. 25.2%) and that reactivity steadily increased with age, peaking after the age of 60. We discuss the paradox of similar infection rates but much lower disease prevalence in women, considering the current pathogenetic views of paracoccidioidomycosis, and we raise alternative hypotheses to account for this paradox.