Highly pathogenic avian influenza (HPAI) A(H5N1) clade 2.3.4.4b virus continues to spread globally and sporadically transmits from avian reservoirs to mammalian hosts. In May 2024, H5N1 infections in young goats and alpacas in the United States were reported. Nevertheless, the overall susceptibility of camelids to clade 2.3.4.4b virus remains unclear. We conducted a controlled experimental infection study in 6 alpacas, assessing clinical signs, viral shedding, tissue distribution, and serologic responses after intranasal inoculation with HPAI H5N1 genotype B3.13 virus. Observed illness was generally mild; body temperature increased slightly and food intake reduced for up to 3 days postinfection. We detected viral RNA in nasal swab samples and confirmed infectious HPAI H5N1 virus. Immunohistochemistry and RNA in situ hybridization detected virus only in the nasopharyngeal tonsil and nasal conchae at 4 days postinfection. Our findings suggest alpacas are susceptible to productive H5N1 infection, highlighting implications for livestock surveillance and biosecurity in regions with ongoing circulation.