Patients (n = 231) diagnosed with solid tumors and undergoing chemotherapy were randomly assigned to the experimental arm (n = 114) or to conventional care (n = 117). A symptom severity index based on summed severity scores across 15 symptoms was the primary outcome. Building on previously published work, an analysis was undertaken to determine the effects of patient characteristics and treatment complications on reductions in symptom severity achieved by a trial of a cognitive-behavioral intervention (CBI). The impact of the intervention on symptom severity differed by the occurrence of neutropenic events, chemotherapy dose delays or dose reductions, and number of comorbid conditions. Patients with more comorbid conditions, as well as those who did not experience neutropenia or dose delay/reduction, who received the intervention reported lower severity at 20 weeks compared to those who received conventional care. This research begins to specify the clinical conditions under which CBIs are effective in lowering symptom severity.