The role of isoprene as a source of secondary organic aerosol (SOA) is studied using laboratory-derived SOA yields and the U.S. Environmental Protection Agency regional-scale Community Multiscale Air Quality (CMAQ) modeling system over a domain comprising the contiguous United States, southern Canada, and northern Mexico. Isoprene is predicted to be a significant source of biogenic SOA, leading to increases up to 3.8 μg m−3 in the planetary boundary layer (PBL, defined as 0–2.85 km) and 0.44 μg m−3 in the free troposphere over that in the absence of isoprene. While the addition of isoprene to the class of SOA-forming organics in CMAQ increases appreciably predicted fine-particle organic carbon (OC2.5) in the eastern and southeastern U.S., total OC2.5 is still underpredicted in these regions. SOA formation is highly sensitive to the value of the enthalpy of vaporization of the SOA. The role of isoprene SOA is examined in a sensitivity study at values of 42 and 156 kJ mol−1; both are commonly used in 3-D aerosol models. Prediction of ambient levels of SOA in atmospheric models remains a challenging problem because of the importance of emissions inventories for SOA-forming organics, representation of gas phase atmospheric chemistry leading to semivolatile products, and treatment of the physics and chemistry of aerosol formation and removal.