Response to primary treatment in diffuse large B-cell lymphoma (DLBCL) is highly predictive of long-term outcome. We evaluated the value of computed tomography (CT) findings relative to positron emission tomography (PET) findings, after the completion of chemotherapy. We retrospectively reviewed records from 491 patients with DLBCL at M. D. Anderson in 2001-2007; 22 patients were excluded for uncertain pathology and 169 for having received consolidative radiation, leaving 300 patients for the present analysis (median age, 61 years; 53% men, 47% women; 27% stage I-II, 73% stage III-IV; 73% completed 6-8 cycles of doxorubicin-based therapy). Factors associated with outcome on univariate analysis were response according to PET/CT and CT (p < 0.0001 for overall survival [OS], disease-specific survival [DSS] and progression-free survival [PFS]); number of chemotherapy cycles received (p < 0.0001 OS, p < 0.0001 DSS, p < 0.002 PFS); the combined presence of Ki-67 > 50%, PET SUV ≥ 13 and bulky (> 5 cm) disease (p = 0.005 OS, p = 0.001 DSS, p = 0.001 PFS); and International Prognostic Index (IPI) score (p = 0.004 OS, p = 0.005 DSS, p = 0.004 PFS). On multivariate analysis, PET/CT-negative, CT residual mass (> 2 cm) significantly influenced OS, DSS and PFS (p < 0.0001). The presence of a residual mass >2 cm on CT, coupled with negative findings on PET/CT, has prognostic value in DLBCL.