Government reports have persistently indicated the intent of terrorists and hostile nations to acquire and "weaponize" nuclear materials for deliberate attack on a major US metropolitan city. A modeling analysis of the effects of 20- and 550-kiloton nuclear detonations on the 2 major metropolitan centers of Los Angeles and Houston is presented with a focus on thermal casualties. Brode's work as modified by Binninger was used to calculate thermal fluence, using thermal fractions. The EM-1 and WE programs were used to calculate blast effects. Fallout radiation was calculated using the Defense Threat Reduction Agency's Hazard Prediction and Assessment Capability V404SP4 with "urban effects" turned on. The ESRI ArcView program calculated affected populations from 2000 US Census block-level data for areas affected by thermal effects. The population affected by a 550-kiloton nuclear weapon detonated in Los Angeles and Houston is staggering: surviving thermal casualties are estimated at 185,000 and 59,000, respectively. Even the 20-kiloton detonations in Los Angeles and Houston are significant: the numbers of surviving thermal casualties requiring care exceed 28,000 and 10,000, respectively. The surviving health care community postdetonation would be faced with an unprecedented burden of care for thermal casualties. A great expansion of personnel involved in emergency burn care response is critical. Bold, new approaches such as regionalization and predetermined medical air transport need to be considered.