A double‐blind study was carried out to evaluate the relative performance and reliability of the PCR/SSOP assay compared to conventional serological typing in identifying HLA‐DR alleles. A total of 268 consecutive samples were entered into the study. In 14 (5.2%) of the cases, HLA‐DR serology could not be performed due to poor cell viability, while in seven (2.6%) of the cases, PCR/SSOP typing could not be performed due to poor amplification or to contamination with exogenous DNA. Among samples that were successfully typed by both methods, serologic typing correctly identified 455/465 (97.9%) DR antigens, while PCR/SSOP correctly identified 464/465 (99.8%) DR alleles (p = 0.0117, McNemar's test). The majority of discrepancies in serologic typing resulted from a lack of discriminative alloantisera to identify DR6 or DR103. For the overall sample set (N = 268), serology provided accurate results in 244 (91.0%) cases, while PCR/SSOP provided accurate results in 260 (97.0%) cases (p = 0.0037). The results of this study demonstrate that PCR/SSOP typing for HLA‐DRB1 alleles provides results that are equal to or surpass serological typing for HLA‐DR antigens. In addition, the PCR/SSOP approach offers the advantages of better reagent availability, lower cost, more rapid turn‐around time, and greater accuracy, all of which would warrant its use as an HLA typing method of choice.