We evaluated the productivity and profitability of four highly productive poplars including Populus deltoides × P. deltoides (DD ‘140’ and ‘356’), P. deltoides × P. maximowiczii (DM ‘230’), and P. trichocarpa × P. deltoides (TD ‘185’) under two densities (2500 and 5000 trees ha−1), and three fertilization treatments (0, 113, 225 kg nitrogen ha−1) at three sandy coastal sites varying in soil quality. Green stem biomass (GSB) was estimated from the sixth-year stem diameter. Leaf-rust (Melampsora castagne) and beetle damage (by Chrysomela scripta Fabricius), the leaf area index (LAI) and foliar nitrogen, were measured in year two. At all sites, DD and DM had higher survival (>93%) than TD (62–83%). DD produced greater GSB (92.5–219.1 Mg ha−1) than DM (54–60.2 Mg ha−1) and TD (16.5–48.9 Mg ha−1), and this was greater under the higher density (85.9–148.6 Mg ha−1 vs. 55.9–124.9 Mg ha−1). Fertilization significantly increased GSB on fertile soil but not marginal soils; a higher rate did not significantly enhance GSB. Leaf rust was higher for fertile soil (82%) than marginal soils (20–22%), and TD ‘185’ (51% vs. others 34%). C. scripta damage was higher for the higher density (+42%) than lower density, and TD ‘185’ (50% vs. others >38%). LAI was higher on fertile soil (1.85 m2 m−2) than marginal soils (1.35–1.64 m2 m−2), and under the lower density (1.67 m2 m−2 vs. 1.56 m2 m−2). The high GSB producer DD ‘356’ had the lowest LAI (1.39 m2 m−2 vs. 1.80 m2 m−2). Foliar nitrogen varied among genomic groups (DD ‘140’ 1.95%; TD ‘185’ 1.80%). Our plots were unprofitable at a 27 USD Mg−1 delivered price; the biggest profitability barriers were the high costs of higher density establishment and weed control. The best-case treatment combinations of DD (‘140’, ‘356’) would be cost-effective if the price increased by 50% (USD 37.54 Mg−1) or rotations were 12 years (fertile-soil) and longer (marginal soils). The requirement for cost-effectiveness of poplars includes stringent and site-specific weed control which are more important than fertilizer applications.