Anti-PD-1 agents, alone or in combination with ipilimumab, produce durable responses in some melanoma patients. Tumor features that correlate with response are not well defined. We collected clinical data from metastatic melanoma patients treated at 2 centers who received anti-PD-1 (n=303) or anti-PD-1+ipilimumab (n=57). We correlated number of metastases, diameter of largest tumor (tumor bulk), and organ involvement with response rate (RR), progression-free survival (PFS), and overall survival (OS). Patients with diameter of largest tumor ≤2 cm had a 53% RR, whereas those with largest tumor >2 cm had a 38% RR (P=0.009). Those with liver metastases had lower RR (25% vs. 43%; P=0.002). RR to anti-PD-1 was greater in patients with ≤10 metastases compared with those with >10 (39% vs. 27%; P=0.027). In multivariable analyses, size of the largest tumor was independently associated with PFS (P=0.0005), OS (P<0.0001), and RR (P=0.02), whereas AJCC stage, lactate dehydrogenase, liver metastases, ECOG performance status, number of metastases, and prior therapies were not. In patients treated with anti-PD-1+ipilimumab, however, tumor bulk was not associated with outcomes, although number of metastases was associated with PFS (P=0.035) and RR (P=0.009) but not OS. Pathologic analysis did not reveal differences in T-cell infiltration in bulky versus small tumors. Tumor bulk, defined by diameter of largest tumor, was strongly and independently associated with clinical outcomes in anti-PD-1 but not in anti-PD-1+ipilimumab. In conjunction with molecular biomarkers, clinical predictors may help guide selection of immunotherapy agents.