The present study aimed to evaluate whether knowledge-based plans (KBP) from a single optimization could be used clinically, and to compare dose-volume histogram (DVH) parameters and plan quality between KBP with (KBPCONST) and without (KBPORIG) manual objective constraints and clinical manual optimized (CMO) plans for pharyngeal cancer. KBPs were produced from a system trained on clinical plans from 55 patients with pharyngeal cancer who had undergone intensity-modulated radiation therapy or volumetric-modulated arc therapy (VMAT). For another 15 patients, DVH parameters of KBPCONST and KBPORIG from a single optimization were compared with CMO plans with respect to the planning target volume (D98%, D50%, D2%), brainstem maximum dose (Dmax), spinal cord Dmax, parotid gland median and mean dose (Dmed and Dmean), monitor units and modulation complexity score for VMAT. The Dmax of spinal cord and brainstem and the Dmed and Dmean of ipsilateral parotid glands were unacceptably high for KBPORIG, although the KBPCONST DVH parameters met our goal for most patients. KBPCONST and CMO plans produced comparable DVH parameters. The monitor units of KBPCONST were significantly lower than those of the CMO plans (P < 0.001). Dose distribution of the KBPCONST was better than or comparable to that of the CMO plans for 13 (87%) of the 15 patients. In conclusion, KBPORIG was found to be clinically unacceptable, while KBPCONST from a single optimization was comparable or superior to CMO plans for most patients with head and neck cancer.