Summary. Objectives: To evaluate the clinical accuracy of antiphospholipid antibody (aPL) specificities both individually and/or in combination, in a wide cohort of systemic lupus erythematosus (SLE) patients in an attempt to identify a panel of tests that may provide the best accuracy for diagnosing antiphospholipid syndrome (APS). Patients and Methods: This study included 230 patients (218 women, mean age 42.7 ± 11.9 years, mean disease duration 12.2 ± 8.7 years), all fulfilling the 1982 criteria for SLE. All patients were tested for lupus anticoagulant (LA), anti-cardiolipin (aCL), anti-β2glycoprotein I (anti-β2GPI), solid phase anti-prothrombin (aPT), anti-phosphatidylserine/prothrombin (aPS/PT), and anti-phosphatidylethanolamine (aPE) antibodies. Sensitivity, specificity and predictive values were calculated. The diagnostic accuracy for each combination of tests was assessed by ROC and their area under the curve analysis as well as by the Youden’s index (YI). Results: Testing for six aPL derived 23 possible combinations of results. Among them, LA + anti-β2GPI + aPS/PT had the best diagnostic accuracy for APS as a whole and individually for both thrombosis and pregnancy loss (AUC 0.712, OR 3.73 [95% CI 1.82–5.38], P = 0.0001, YI = 0.32 and AUC 0.709, OR 3.75 [95% CI 2.13–6.62], P = 0.0001, YI = 0.37 and AUC 0.677, OR 4.82 [95% CI 2.17–10.72], P = 0.0007, YI = 0.38, respectively) and the best specificity when compared with all the other obtainable combination of tests. Triple positivity for LA + anti-β2GPI + aPS/PT was more strongly associated with clinical events (thrombosis and/or PL) when compared with double or single positivity (OR 23.2 [95% CI 2.57–46.2] vs. OR 7.3 [95% CI 2.21–25.97], OR 5.7 [95% CI 2.12–17.01] or OR 3.11 [95% CI 1.56–7.8] for single positivity for LA, aPS/PT and anti-β2GPI, respectively). Conclusions: Combining LA, anti-β2GPI and aPS/PT improves the diagnostic power and helps in stratifying the risk for each patient, according to their aPL profile.