BACKGROUND: Penicillium marneffei is an emerging dimorphic mycosis endemic in Southeast Asia, and a leading cause of mortality among human immunodeficiency virus (HIV)-infected people in the region. Factors governing the seasonal incidence of P. marneffei infection are unknown, and may yield critical insights into possible reservoirs or modes of acquisition. METHODS: This study included HIV-infected patients presenting with P. marneffei (n = 719) and Cryptococcus neoformans (n = 1598) infection to the Hospital for Tropical Diseases in Ho Chi Minh City, Vietnam, from 2004 to 2010, and temperature, humidity, wind, precipitation, and HIV-related admissions data for the corresponding period. We used multivariate regression modeling to identify factors associated with P. marneffei and C. neoformans admissions. We estimated the P. marneffei incubation period by considering profile likelihoods for different exposure-to-admission delays. RESULTS: We found that P. marneffei admissions were strongly associated with humidity (P < .001), and that precipitation, temperature, and wind did not add explanatory power. Cryptococcus neoformans admissions were not seasonal, and P. marneffei admissions were more common relative to C. neoformans admissions during months of high (≥85%) humidity (odds ratio, 1.49; 95% confidence interval [CI], 1.10-2.01). Maximum likelihood estimation suggested a P. marneffei incubation period of 1 week (95% CI, 0-3 weeks). CONCLUSIONS: Our findings suggest that humidity is the most important environmental predictor of P. marneffei admissions, and may drive exposure by facilitating fungal growth or spore release in the environment. In addition, it appears that a high proportion of penicilliosis patients present to the hospital with primary disseminated infection within 3 weeks of exposure.