Cnidoscolus monicanus J. A. Lomelí, Sahagún & V. W. Steinmann (Euphorbiaceae), endemic to western Mexico, is described and illustrated. This new species belongs to Cnidoscolus Pohl sect. Calyptrosolen (Müller Argoviensis ex Pax) Pax & K. Hoffmann and is closely allied to C. elasticus Lundell and C. tepiquensis (Costantin & Gallaud) McVaugh. We provide an identification key to the C. tepiquensis complex. These species share an arborescent and little or non-urticating habit at maturity, inflorescences that are often unisexual, and large seeds. We hypothesize that these species constitute a monophyletic group within section Calyptrosolen. Cnidoscolus monicanus is characterized by the following combination of characters: tree with grayish non-exfoliating bark and verticillate branching, petioles with two discrete glands projecting outward from the epidermis, leaf laminas (16–)20–41(–60) × (25–) 36–67(–75) cm, leaf margins entire or with a few obscure to rarely caudate teeth, staminate flowers with a pubescent zone on the staminal column 3–4 mm long, pistillate flowers with a tomentulose perianth, a tomentose to sericeous ovary, peduncles of the pistillate infructescence 1.7–5 cm long, capsule with distal ribs and an acute apex, pedicels 5–20 mm long, and seeds 24–32 mm long. The new species occurs at elevations of 750–1640 m in tropical deciduous and semideciduous forest. We applied the Method for Evaluation of Risk Extinction for Wild Species in Mexico (MER) to estimate the conservation status of C. monicanus, and we concluded that it is threatened. We also evaluated the new species using applicable IUCN criteria and found it to be Endangered (EN).