Hel-NI and HuD belong to the elav gene family and have gained recent attention as potential neuroendocrine markers for small-cell lung carcinoma (SCLC). Members of this conserved family normally appear at different stages of neuronal maturation, raising the possibility that their expression patterns in SCLC reflect the degree of neuroendocrine differentiation. I have utilized a ribonuclease protection assay to analyze Hel-NI and HuD expression in cultured SCLC cells with high (classic phenotype) and low (variant phenotype) levels of neuroendocrine differentiation. Hel-NI was detected in both classic and variant SCLC. Although HuD was detected consistently in classic SCLC, it was low to absent in variant SCLC, indicating a significant down-regulation in that phenotype. The expression patterns of Hel-NI and HuD also were analyzed in 9 primary SCLC and 10 non-SCLC lung-tumor samples. In the majority of SCLC samples, either Hel-NI or HuD was detected exclusively or predominantly, indicating a pattern of variable gene expression similar to cultured SC LC. Neither transcript could be detected in the non-SCLC samples. These data indicate that (i) HuD mRNA expression is associated with a higher level of neuroendocrine differentiation in SCLC, (ii) Hel-NI and HuD expressions are variable in both primary and cultured SCLC and (iii) HuD and Hel-NI, in combination, are neurogenetic markers for SCLC.