F-DCFPyL, F-sodium fluoride (F-NaF), and F-FDG PET/CT were compared in a prospective cohort of men with metastatic prostate cancer (PCa). Sixty-seven men (group 1) with documented metastatic PCa underwent F-DCFPyL and F-NaF PET/CT and a subgroup of 30 men (group 2) underwent additional imaging with F-FDG PET/CT. The tracers were compared for their detection rates, imaging concordance, associations with prostate-specific antigen (PSA), treatment at the time of imaging, and castration status. Overall, 61 men had metastatic disease detected on one or more scans, and 6 men had no disease uptake on any of the PET/CT scans (and were subsequently excluded from the analysis). In group 1, F-NaF detected significantly more metastatic lesions than F-DCFPyL (median of 3 lesions vs. 2, = 0.001) even after eliminating benign causes of F-NaF uptake. This difference was particularly clear for men receiving treatment ( = 0.005) or who were castration-resistant ( = 0.014). The median percentage of bone lesions that were concordant on F-DCFPyL and F-NaF was 50%. In group 2, F-DCFPyL detected more lesions than F-FDG (median of 5 lesions vs. 2, = 0.0003), regardless of PSA level, castration status, or treatment. The median percentage of lesions that were concordant on F-DCFPyL and F-FDG was 22.2%. This percentage was slightly higher for castration-resistant than castration-sensitive men ( = 0.048). F-DCFPyL PET/CT is the most versatile of the 3 PET agents for metastatic PCa; however, F-NaF detects more bone metastases. Imaging reveals substantial tumor heterogeneity with only 50% concordance between F-DCFPyL and F-NaF and 22% concordance for F-DCFPyL and F-FDG. These findings indicate considerable phenotypic differences among metastatic lesions.