Objectives The Strengthening Families Programme 10–14 (SFP10-14) is a USA-developed universal group-based intervention aiming to prevent substance misuse by strengthening protective factors within the family. This study evaluated a proportionate universal implementation of the adapted UK version (SFP10-14UK) which brought together families identified as likely/not likely to experience/present challenges within a group setting. Design Pragmatic cluster-randomised controlled effectiveness trial, with families as the unit of randomisation and embedded process and economic evaluations. Setting The study took place in seven counties of Wales, UK. Participants 715 families (919 parents/carers, 931 young people) were randomised. Interventions Families randomised to the intervention arm received the SFP10-14 comprising seven weekly sessions. Families in intervention and control arms received existing services as normal. Outcome measures Primary outcomes were the number of occasions young people reported drinking alcohol in the last 30 days; and drunkenness during the same period, dichotomised as ‘never’ and ‘1–2 times or more’. Secondary outcomes examined alcohol/tobacco/substance behaviours including: cannabis use; weekly smoking (validated by salivary cotinine measures); age of alcohol initiation; frequency of drinking $>$5 drinks in a row; frequency of different types of alcoholic drinks; alcohol-related problems. Retention: primary analysis included 746 young people (80.1%) (alcohol consumption) and 732 young people (78.6%) (drunkenness). Results There was no evidence of statistically significant between-group differences 2 years after randomisation for primary outcomes (young people’s alcohol consumption in the last 30 days adjusted OR=1.11, 95% CI 0.72 to 1.71, p=0.646; drunkenness in the last 30 days adjusted OR=1.46, 95% CI 0.83 to 2.55, p=0.185). There were no statistically significant between-group differences for other substance use outcomes, or those relating to well-being/stress, and emotional/behavioural problems. Conclusions Previous evidence of effectiveness was not replicated. Findings highlight the importance of evaluating interventions when they are adapted for new settings. Trial registration number ISRCTN63550893 .Cite Now