INTRODUCTION: The M6 risk prediction model has been shown to have good triage performance for stratifying women with a PUL as being at low or high-risk of harboring an ectopic pregnancy. There is evidence that M6 has better overall test performance than the hCG ratio (serum hCG at 48 hours/hCG at presentation) and older models such as the M4 model. M6 was published as part of a two-step protocol using an initial progesterone ≤2nmol/l to identify likely failing pregnancies (step 1), followed by M6 (step 2). This study validated the triage performance of this protocol in clinical practice by evaluating (1) the number of protocol-related adverse events and (2) how patients are effectively triaged. METHODS: This was a prospective multi-centre interventional study of 3272 women with a PUL carried out between January 2015 and January 2017 in four district general hospitals and four university teaching hospitals in the United Kingdom. We defined the final pregnancy outcome as: a failed PUL (FPUL), an intrauterine pregnancy (IUP) or an ectopic pregnancy (EP) (including persistent PUL (PPUL)). FPUL and IUP were grouped as low-risk and EP and PPUL as high-risk PUL. Patients had a serum progesterone and hCG level at 0 hours and repeat hCG at 48 hours. In seven centres, if the initial progesterone was ≤2nmol/l, patients were discharged with a follow-up urine pregnancy test in two weeks to confirm a negative result. If the progesterone was >2nmol/l or had not been taken, a 48 hour hCG level was taken and results entered into the M6 model. Patients were managed according to their predicted outcome: those classified with pregnancies likely to resolve (FPUL) were advised to perform a urine pregnancy test in two weeks and those with a likely IUP were invited for a scan a week later. When a women with a PUL was classified as high-risk (i.e. those with a risk of EP ≥ 5%) were reviewed clinically within 48 hours. One centre used a progesterone cut-off ≤10nmol/l and was analysed separately. If the recommended management protocol was not adhered to, this was recorded as an 'unscheduled visit (participant reason)', 'unscheduled visit (clinician reason)' or 'differences in timing (blood test/ultrasound)'. The classifications outlined in UK Good Clinical Practice guidelines were used to evaluate adverse events. Data were analysed with descriptive statistics. RESULTS: Data was available for main analysis in 2625/3272 women with PUL (317 met the exclusion criteria or were lost to follow-up, 330 were evaluated with a progesterone cut-off of ≤10nmol/l). Progesterone results were available for 2392 (91%). 407 (15.5%) patients were classified as low-risk at step 1 (progesterone ≤2nmol/l), of which 7 (1.7%) were ultimately diagnosed with an EP. For 279/2218 remaining women with a PUL, M6 was not used or the outcome was already known usually on the basis of an ultrasound scan before a second hCG level was taken (30 were EP). 1038 women with a PUL were classified as low-risk at step 2, of which 8 (0.8%) were EP. 901 women with a PUL were classified as high-risk at step 2, of which 275 (30.5%) were EP. 275/320 (85.9%) EP were correctly classified as high-risk. Overall, 1445/2625 PUL (55.0%) were classified as low-risk, of which 15 (1.0%) were EP. None of these 15 EP ruptured. CONCLUSIONS: This study has shown that the two-step protocol incorporating the M6 model effectively triaged a majority of women with a PUL as being at low-risk of an EP, minimizing the follow-up required for these patients after just two visits. There were few misclassified EP and none of these women came to significant clinical harm or suffered a serious adverse clinical event. The two-step protocol, incorporating the M6 model, is an effective and clinically safe way of rationalizing the management of women with a PUL.