Abstract Objectives To determine an US scanning protocol with the best accuracy for the diagnosis of gout and CPPD in patients with acute mono/oligo-arthritis of unknown origin. Methods Patients with acute mono/oligo-arthritis in whom a joint aspiration at the most clinically involved joint (target joint) was requested were consecutively enrolled. US was performed in each patient before the arthrocentesis. The accuracy of different US findings and scanning protocols for the diagnosis of gout and CPPD was calculated. Results A total of 161 subjects were included (32 gout patients, 30 CPPD patients and 99 disease-controls). US findings had a high specificity for gout (0.92–0.96) and CPPD (0.90–0.97), while the sensitivity ranged from 0.73 to 0.85 in gout (double contour sign and tophi, respectively) and from 0.60 to 0.90 in CPPD (hyaline and fibrocartilage deposits, respectively). The US assessment of two joints bilaterally (gout: knees, MTP1 joints; CPPD: knees, wrists) plus the target joint had an excellent diagnostic sensitivity (gout: 0.91, CPPD: 0.93) and specificity (gout: 0.91, CPPD: 0.89). This targeted US scanning protocol yielded to higher diagnostic accuracy compared with the US evaluation of the target joint [gout area under the curve (AUC) 0.91 vs 0.84, P = 0.03; CPPD AUC 0.93 vs 0.84, P = 0.04] unless the target joint was the knee or the MTP1 joint in gout and the knee or the wrist in CPPD. Conclusions A targeted US scanning protocol of two joints bilaterally plus the target joint showed an excellent accuracy (>90%) for the diagnosis of crystal arthritis in patients with acute mono/oligoarthritis.