Background. First impressions are thought to exert a disproportionate influence on subsequent judgments; however, their role in medical diagnosis has not been systematically studied. We aimed to elicit and measure the association between first impressions and subsequent diagnoses in common presentations with subtle indications of cancer. Methods. Ninety UK family physicians conducted interactive simulated consultations online, while on the phone with a researcher. They saw 6 patient cases, 3 of which could be cancers. Each cancer case included 2 consultations, whereby each patient consulted again with nonimproving and some new symptoms. After reading an introduction (patient description and presenting problem), physicians could request more information, which the researcher displayed online. In 2 of the possible cancers, physicians thought aloud. Two raters coded independently the physicians’ first utterances (after reading the introduction but before requesting more information) as either acknowledging the possibility of cancer or not. We measured the association of these first impressions with the final diagnoses and management decisions. Results. The raters coded 297 verbalizations with high interrater agreement (Kappa = 0.89). When the possibility of cancer was initially verbalized, the odds of subsequently diagnosing it were on average 5 times higher (odds ratio 4.90 [95% CI 2.72 to 8.84], P < 0.001), while the odds of appropriate referral doubled (OR 1.98 [1.10 to 3.57], P = 0.002). The number of cancer-related questions physicians asked mediated the relationship between first impressions and subsequent diagnosis, explaining 29% of the total effect. Conclusion. We measured a strong association between family physicians’ first diagnostic impressions and subsequent diagnoses and decisions. We suggest that interventions to influence and support the diagnostic process should target its early stage of hypothesis generation.