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In contrast to other countries with predominantly white populations, Russian smoking-related lung cancers (LC) are mainly squamous cell carcinomas and approximately half lung adenocarcinomas (AdCa) are not related to tobacco consumption. Given that smoking significantly influences the probability of presence of actionable mutations in LC, one would expect that Russian lung AdCa patients would differ from other white populations in distribution of EGFR, ALK, KRAS and BRAF mutations. Herein, 2,336 consecutive lung AdCa cases, including 1,203 patients with known smoking status, were subjected to sequential testing for the above mutations. One quarter of lung AdCa patients carried either EGFR or ALK mutation with combined prevalence of 42% in those who had never smoked but only 8% in smokers. There was only a moderate difference in KRAS mutation frequency between ever- and never-smokers in EGFR/ALK-negative cases (31% vs. 23%), and this was mainly attributed to increased prevalence of G12C substitution in the former group. The occurrence of BRAF V600E mutation was 1.7% and 4% in EGFR/ALK/KRAS mutation-negative ever- and never-smokers, respectively. ALK testing of 470 EGFR-mutated tumors revealed only 1 (0.2%) instance of translocation. Similarly, KRAS testing identified 1 (1.25%) mutation in 80 EGFR-mutated AdCa and none in 48 ALK-rearranged AdCa. Therefore, concurrent actionable mutations in lung adenocarcinoma are exceptionally rare and sequential gene testing can be regarded as a reliable option.